CN101277611A - Pharmaceutical formulation - Google Patents

Pharmaceutical formulation Download PDF

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CN101277611A
CN101277611A CNA2006800361338A CN200680036133A CN101277611A CN 101277611 A CN101277611 A CN 101277611A CN A2006800361338 A CNA2006800361338 A CN A2006800361338A CN 200680036133 A CN200680036133 A CN 200680036133A CN 101277611 A CN101277611 A CN 101277611A
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gly
glu
lys
asp
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M·T·李
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Kai Pharmaceuticals Inc
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Kai Pharmaceuticals Inc
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    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
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Abstract

A pharmaceutical formulation for a PKC modulatory peptide and a transport moiety comprising the aforementioned components and an anti-aggregant.

Description

Pharmaceutical preparation
Technical field
[0001] the present invention relates to pharmaceutical preparation, particularly the preparation of amino acid, peptide and small protein is specifically related to PKC peptide/transporter bond (conjugate, conjugate, attachment, preparation conjugate).
Background technology
[0002] protein kinase C (" PKC ") relates to the key enzyme in the signal transduction of various kinds of cell function, and described cell function comprises the adjusting and the ion channel activity of cell growth, gene expression.PKC isodynamic enzyme family comprises at least 10 kinds of different protein kinases, and based on their autoploidy with to the susceptibility of activator, they can be divided at least 3 subfamilies (referring to Fig. 1).Each isodynamic enzyme comprises a large amount of homologies (" guarding " or " C ") domain, and is scattered with isodynamic enzyme-distinctive (" variable " or " V ") domain." typically " subfamily member---α (SEQ ID NO:164), β I(SEQ ID NO:165), β II(SEQ ID NO:166) and γ PKC (SEQ ID NO:167) comprise four homeodomains (C1, C2, C3 and C4), and need calcium, phosphatidyl serine and DG or Buddhist ripple ester, activate." novel " subfamily member---δ (SEQ ID NO:168), ε (SEQ ID NO:169), η (SEQ ID NO:170) and θ PKC (SEQ ID NO:171) lack the C2 homeodomain, and its activation does not need calcium.At last, atypical subfamily member---ζ (SEQ ID NO:174) and λ/ ιPKC (SEQID NO:172) lacks half of C2 and C1 homeodomain, and insensitive to DG, Buddhist ripple ester and calcium.
[0003] single PKC isodynamic enzyme relates to the mechanism of various disease states, comprises following: cancer (α and δ PKC); Cardiac hypertrophy and heart failure (β I and β II PKC); Injury sensation (γ and ε PKC); The ischaemic (δ and ε PKC) that comprises miocardial infarction; Immune response, particularly T-cell-mediated immune responses (θ PKC); With fibroblastic growth and memory (ζ PKC).
Summary of the invention
[0004] according to the target of listing above, invention of the present disclosure provides protein kinase C to regulate the pharmaceutical preparation of peptide and cation (promptly positively charged) transit peptides and anti-aggregating agent prepared therefrom (anti-aggregant).Preferred anti-aggregating agent prepared therefrom is a sugar, it is characterized by (stereochemically aligned) hydroxylic moiety with sufficient amount spatial chemistry location, to interact with adjusting peptide and/or the hydrophobic and/or positively charged part of transit peptides, so that promote itself and anti-aggregating agent prepared therefrom group structure, rather than assemble each other.PKC regulates peptide, and for example the peptide of deriving from various PKC variable region constitutes preferred embodiment.The cation transfer of Shi Yonging partly comprises cationic peptide in the present invention, as pR60 and HIV-tat.Particularly preferred embodiment comprises the transit peptides that PKC peptide for inhibiting and HIV-tat derive.The example of this embodiment is KAI-9803 (SEQ ID NO:1).
[0005] in a particular aspects of said medicine preparation, the ratio ranges of anti-aggregating agent prepared therefrom and peptide/transporter bond was from about 100: 1 to about 1: 1,90: 1,80: 1,70: 1,60: 1,50: 1,40: 1,30: 1,20: 1,10: 1,5: 1 and 1: 1.
[0006] another aspect of the present invention provides stable drug products, and to transport before use and to store, described stable medicine comprises the lyophilized cake piece (lyophilized cake) of interior KAI-9803 of airtight container and anti-aggregating agent prepared therefrom.Freeze-drying prods preferably obtains from the solution of KAI-9803 and acetate equilibrium ion (acetate counterion).The ratio of KAI-9803 and anti-aggregating agent prepared therefrom is from about 1: 5 to about 1: 100, and about especially 1: 80, and especially about 1: 8.Anti-aggregating agent prepared therefrom is sugar preferably.This concrete series products is 5mg KAI-9803 and the 40mg mannitol in the good vial of plug.The reconstruct specification preferably be incorporated into container or the label, external packing and/or the packing insert that adhere on it on.
[0007] another aspect of the present invention provides the preparation of parenteral (particularly in the hat) administration, it is the KAI-9803 of about 2.5mg/mL and the mannitol of about 20mg/mL, by using sodium chloride for injection, USP (preferred 0.9%) is reconstructed into about 0.001 to 2.5mg/mL, preferably about 0.01 to the prepared at concentrations of 1.0mg/mL and get with the lyophilized cake piece.For the reconstruct lyophilized formulations to carry out administration, the airtight container that product at first will be housed is warming up to room temperature, add pharmaceutically acceptable solvent (salt solution for example with the amount that is enough to dissolve the lyophilized cake piece afterwards, preferred 9% salt solution), then, the solvent that adds this class additional quantity when needed is to obtain being used for the expectation concentration of administration.
[0008] the present invention is the preparation method in addition on the other hand, may further comprise the steps:
(A) the anti-aggregating agent prepared therefrom of appropriate amount, hydrophobic active agent and/or cation transfer part are joined the container (preferred glass bottle) of suitable size as dried solid.
(B) pharmaceutically acceptable solvent is joined in the container with the amount that is enough to dissolve this solid.
The solution lyophilization that (C) will so form.
(D) with seal of vessel (randomly after at first for example nitrogen is filled head space with non-active gas).
[0009] by reading following detailed, others and embodiment will be clearly to those of ordinary skills.
The accompanying drawing summary
[0010] Fig. 1 shows the schematic diagram of three families of protein kinase C isodynamic enzyme.
[0011] Fig. 2 shows that the δ pkc inhibitor KAI-9803 that quantity is increased replys and the figure of the total unit of creatine kinase that discharges.
[0012] Fig. 3 illustrates the figure of the infarct size percentage of whole tissues, responds to the δ pkc inhibitor KAI-9803 that quantity increases.
[0013] image shown in Fig. 4 has compared with the blood flow in the tissue sample of KAI-9803 treatment with the blood flow in the tissue of control formulation treatment.
Embodiments of the present invention
[0014] invention of describing at present relates to the pharmaceutical preparation of the peptide of regulating one or more protein kinase C activity of isoenzyme.In some embodiments, peptide described herein is connected to carrier part and is transported to target cell to help regulating peptide.Generally speaking, the preferred implementation of pharmaceutical preparation of the present disclosure further comprises anti-aggregating agent prepared therefrom and one or more excipient.Comprise the pharmaceutical preparation of regulating peptide active pharmaceutical ingredient processing, preparation production, stability, concentration and easy-to-use aspect advantage is provided.These and other advantage is more detailed description below.
Definition
[0015] as using in this manual, the common draw up of following vocabulary and phrase has the implication of setting forth below, except situation about indicating in addition in the context that uses them.
[0016] " PKC regulates peptide " or " regulating the peptide of one or more protein kinase C activity of isoenzyme " refer to promote, strengthen or activate the peptide of one or more PKC isodynamic enzymes, perhaps can also suppress alternatively or the peptide of one or more PKC isodynamic enzymes of inactivation.
[0017] term " API " refers to active pharmaceutical ingredient, and it is used to refer to PKC in this article and regulates peptide and transhipment part, and it is covalent bond each other, and/or is covalently bound to one or more activating agents.
[0018] term " illness " or " morbid state " refer to any mammalian diseases, illness, symptom or indication, optimize disease, illness, symptom or the indication of present human patients.
[0019] term " effective dose " refers to enough realize the quantity of the API of treatment when API being administered to the mammal that needs this class treatment, and is as described below.
[0020] term " KAI-9803 " refers to the peptide of deriving from first variable region of δ PKC, and it is connected to the HIV Tat-transit peptides of deriving by the Cys-Cys disulfide bond, and can be expressed as followsin:
H 2N-Cys-Ser-Phe-Asn-Ser-Tyr-Glu-Leu-Gly-Ser-Leu-COOH (δ PKC peptide)
|
S
| (disulfide bond)
S
|
H 2N-Cys-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-COOH (transporter)
(SEQ ID NO：1)
[0021] term " optional " or " randomly " refer to that incident or the situation described subsequently can take place or can not take place, and this description comprises the situation that situation that this class incident or situation take place and this class incident or situation do not take place.
[0022] as used herein, " pharmaceutically acceptable carrier " or " pharmaceutically acceptable excipient " comprise arbitrarily and all solvents, dispersion medium, antibacterial agent and antifungal agent, etc. blend absorption delay agent etc.This class medium and being applied in of reagent that are used for pharmaceutically active substance are known in the art.Supplementary active ingredients also can be introduced into said composition.
[0023] term " pharmaceutically acceptable salt " or " equilibrium ion " refer to keep the salt of API biological effectiveness and characteristic, and this salt be not biologically or others disadvantageous.In many cases, because the existence of amino and/or carboxyl or the group similar to them, API can form ackd salt and/or basic salt.Pharmaceutically acceptable base addition salts can be from inorganic and/or organic base preparation.Pharmaceutically-acceptable acid addition can be from inorganic and/or organic acid preparation.For example, inorganic acid comprises hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc.Organic acid comprises acetate, propionic acid, glycolic, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, right-toluene-sulfonic acid, salicylic acid etc.
[0024] term " drug products " refers to API, and it is prepared and be packed in the container, is used to store, transportation or administration.
[0025] term " PKC-derived peptide (PCK-derived peptide) " refers to PKC isodynamic enzyme-and/or variable region-specific peptide, for example in United States Patent (USP) and announcement the 5th, 783,405,6,165,977, US2002/0150984, US2002/0168354, US2002/057413, US2003/0223981, US2004/0009922 number and the interim patent sequence number 60/550 of the U.S. common in a review submitted on March 5th, 2004, describe in 755, all these are incorporated herein by reference with its integral body.
[0026] term " transporter part " refers to help the composition of the API of cellular uptake, and as cationic polymer, peptide and antibody sequence, it comprises many lysines, pR60, feeler foot-derived peptide, HIV Tat-derived peptide etc.An example of transporter part is " transit peptides ", and it is to help cellular uptake PKC to regulate the peptide of peptide, and described PKC adjusting peptide is by chemical association or be attached to transit peptides.
[0027] term " treatment (treatment) " or " treatment (treating) " refer to any treatment to mammalian diseases or illness, comprising: prevent or protect resist the disease or illness, that is to say, clinical symptoms is not taken place; Suppress disease or illness, that is to say, stop or suppress the development of clinical symptoms; And/or palliate a disease or illness, that is to say, make clinical symptoms disappear (regression).
[0028] term " prevention (prophylaxis) " work done in the manner of a certain author is the part of " treatment ", comprises " preventing (preventing) " as herein described and " compacting ".It will be appreciated by those skilled in the art that in the human medicine and always can not distinguish " preventing " and " compacting ", because the final incident (one or more) of inducing may be unknown, potential, perhaps after one or more things took place fully, the patient just determined.
Protein kinase C is regulated peptide
[0029] multiple PKC isodynamic enzyme-and variable region-specific peptide be described and can be used for invention of the present disclosure.Preferably, PKC adjusting peptide is V1, V3 or V5 derived peptide.The multiple suitable peptide that can be used for invention of the present disclosure has been described in following United States Patent (USP) or patent application: 5,783,405,6,165,977,6,855,693, US2004/0204364, US2002/0150984, US2002/0168354, US2002/057413, US2003/0223981, US2004/0009922 and 10/428,280, they each full content is introduced into this paper by reference.Table 1 provides and has been used for the tabulation that preferred PKC of the present invention regulates peptide.
Table 1
The peptide of deriving from the PKC isodynamic enzyme
Peptide SEQ ID NO. Sequence
αV3-1 SEQ ID NO：2 I-P-E-G-D-E-E-G
αV5-1 SEQ ID NO：3 Q-L-V-I-A-N
αV5-1.1 SEQ ID NO：4 G-L-G-A-E-N
αV5-1.2 SEQ ID NO：5 A-R-G-A-E-N
αV5-1.3 SEQ ID NO：6 C-G-K-G-A-E-N
αV5-1.4 SEQ ID NO：7 C-G-K-G-A-E-N
βC2-1 SEQ ID NO：8 K-Q-K-T-K-T-I-K
βC2-2 SEQ ID NO：9 M-D-P-N-G-L-S-D-P-Y-V-K-L
βC2-3 SEQ ID NO：10 I-P-D-P-K-S-E
βC2-4 SEQ ID NO：11 S-L-N-P-E-W-N-E-T
βV3-1 SEQ ID NO：12 V-P-P-E-G-S-E-A
βIV5-1 SEQ ID NO：13 K-L-F-I-M-N
βIV5-2 SEQ ID NO：14 R-D-K-R-D-T-S
βIV5-2.1 SEQ ID NO：15 C-A-R-D-K-R-D-T-S
βIV5-2.2 SEQ ID NO：16 G-R-D-K-R-D-T-S
βIV5-2.3 SEQ ID NO：17 A-R-D-K-R-D-T-S
βIV5-3 SEQ ID NO：18 A-R-D-K-R-D-T-S-N-F-D-K
βIV5-4 SEQ ID NO：19 A-G-F-S-Y-T-N-P-E-F-V-I-N-V
Peptide SEQ ID NO. Sequence
βIIV5-1 SEQ ID NO：20 Q-E-V-I-R-N
βIIV5-2 SEQ ID NO：21 C-G-R-N-A-E
βIIV5-3 SEQ ID NO：22 A-C-G-R-N-A-E
βIIV5-3.1 SEQ ID NO：23 A-C-G-K-N-A-E
βIIV5-4 SEQ ID NO：24 K-A-C-G-R-N-A-E
βIIV5-5 SEQ ID NO：25 C-G-R-N-A-E-N
βIIV5-6 SEQ ID NO：26 A-C-G-R-N-A-E
βIIV5-7 SEQ ID NO：27 S-F-V-N-S-E-F-L-K-P-E-V-L-S
γV3-1 SEQ ID NO：28 V-A-D-A-D-N-C-S
γV5-1 SEQ ID NO：29 G-R-S-G-E-N
γV5-1.1 SEQ ID NO：30 G-L-S-G-E-N
γV5-2 SEQ ID NO：31 R-L-V-L-A-S
γV5-3 SEQ ID NO：32 P-C-G-R-S-G-E-N
δV1-1 SEQ ID NO：33 C-S-F-N-S-Y-E-L-G-S-L
δV1-1.1 SEQ ID NO：34 S-F-N-S-Y-E-L-G-S-L
δV1-1.2 SEQ ID NO：35 T-F-N-S-Y-E-L-G-S-L
δV1-1.3 SEQ ID NO：36 A-F-N-S-N-Y-E-L-G-S-L
δV1-1.4 SEQ ID NO：37 S-F-N-S-Y-E-L-G-T-L
δV1-1.5 SEQ ID NO：38 S-T-N-S-Y-E-L-G-S-L
δV1-1.6 SEQ ID NO：39 S-F-N-S-F-E-L-G-S-L
δV1-1.7 SEQ ID NO：40 S-N-S-Y-D-L-G-S-L
δV1-1.8 SEQ ID NO：41 S-F-N-S-Y-E-L-P-S-L
δV1-1.9 SEQ ID NO：42 T-F-N-S-Y-E-L-G-T-L
δV1-1.10 SEQ ID NO：43 S-F-N-S-Y-E-I-G-S-V
δV1-1.11 SEQ ID NO：44 S-F-N-S-Y-E-V-G-S-I
δV1-1.12 SEQ ID NO：45 S-F-N-S-Y-E-L-G-S-V
δV1-1.13 SEQ ID NO：46 S-F-N-S-Y-E-L-G-S-I
δV1-1.14 SEQ ID NO：47 S-F-N-S-Y-E-I-G-S-L
δV1-1.15 SEQ ID NO：48 S-F-N-S-Y-E-V-G-S-L
δV1-1.16 SEQ ID NO：49 A-F-N-S-Y-E-L-G-S-L
δV1-1.17 SEQ ID NO：50 Y-D-L-G-S-L
δV1-1.18 SEQ ID NO：51 F-D-L-G-S-L
δV1-1.19 SEQ ID NO：52 Y-D-I-G-S-L
δV1-1.20 SEQ ID NO：53 Y-D-V-G-S-L
δV1-1.21 SEQ ID NO：54 Y-D-L-P-S-L
δV1-1.22 SEQ ID NO：55 Y-D-L-G-L-L
δV1-1.23 SEQ ID NO：56 Y-D-L-G-S-I
δV1-1.24 SEQ ID NO：57 Y-D-L-G-S-V
δV1-1.25 SEQ ID NO：58 I-G-S-L
δV1-1.26 SEQ ID NO：59 V-G-S-L
δV1-1.27 SEQ ID NO：60 L-P-S-L
δV1-1.28 SEQ ID NO：61 L-G-L-L
δV1-1.29 SEQ ID NO：62 L-G-S-I
δV1-1.30 SEQ ID NO：63 L-G-S-V
Peptide SEQ ID NO. Sequence
δV1-2 SEQ ID NO：64 A-L-S-T-E-R-G-K-T-L-V
δV1-2.1 SEQ ID NO：65 A-L-S-T-D-R-G-K-T-L-V
δV1-2.2 SEQ ID NO：66 A-L-T-S-D-R-G-K-T-L-V
δV1-2.3 SEQ ID NO：67 A-L-T-T-D-R-G-K-S-L-V
δV1-2.4 SEQ ID NO：68 A-L-T-T-D-R-P-K-T-L-V
δV1-2.5 SEQ ID NO：69 A-L-T-T-D-R-G-R-T-L-V
δV1-2.6 SEQ ID NO：70 A-L-T-T-D-K-G-K-T-L-V
δV1-2.7 SEQ ID NO：71 A-L-T-T-D-K-G-K-T-L-V
δV1-3 SEQ ID NO：72 V-L-M-R-A-A-E-E-P-V
δV1-4 SEQ ID NO：73 Q-S-M-R-S-E-D-E-A-K
δV1-5 SEQ ID NO：163 A-F-N-S-Y-E-L-G-S
δV3-1 SEQ ID NO：74 Q-G-F-E-K-K-T-G-V
δV3-2 SEQ ID NO：75 D-N-N-G-T-Y-G-K-I
δV5-1 SEQ ID NO：76 K-N-L-I-D-S
δV5-2 SEQ ID NO：77 V-K-S-P-R-D-Y-S
δV5-2.1 SEQ ID NO：78 V-K-S-P-C-R-D-Y-S
δV5-2.2 SEQ ID NO：79 I-K-S-P-R-L-Y-S
δV5-3 SEQ ID NO：80 K-N-L-I-D-S
δV5-4 SEQ ID NO：81 P-K-V-K-S-P-R-D-Y-S-N
εV1-1 SEQ ID NO：82 N-G-L-L-K-I-K
εV1-2 SEQ ID NO：83 E-A-V-S-L-K-P-T
εV1-3 SEQ ID NO：84 L-A-V-F-H-D-A-P-I-G-Y
εV1-4 SEQ ID NO：85 D-D-F-V-A-N-C-T-I
εV1-5 SEQ ID NO：86 W-I-D-L-E-P-E-G-R-V
εV1-6 SEQ ID NO：87 H-A-V-G-P-R-P-Q-T-F
εV1-7 SEQ ID NO：88 N-G-S-R-H-F-E-D
εV1-7.1 SEQ ID NO：89 H-D-A-P-I-G-D-Y
εV1-7.2 SEQ ID NO：90 H-D-A-P-I-G
εV1-7.3 SEQ ID NO：91 H-D-A-A-I-G-Y-D
εV1-7.4 SEQ ID NO：92 H-D-A-P-I-P-Y-D
εV1-7.5 SEQ ID NO：93 H-N-A-P-I-G-Y-D
εV1-7.6 SEQ ID NO：94 H-A-A-P-I-G-Y-D
εV1-7.7 SEQ ID NO：95 A-D-A-P-I-G-Y-D
εV1-7.8 SEQ ID NO：96 H-D-A-P-A-G-Y-D
εV1-7.9 SEQ ID NO：97 H-D-A-P-I-G-A-D
εV1-7.10 SEQ ID NO：98 H-D-A-P-I-A-Y-D
εV1-7.11 SEQ ID NO：99 H-D-A-P-I-G-Y-A
εV3-1 SEQ ID NO：100 S-S-P-S-E-E-D-R-S
εV3-2 SEQ ID NO：101 P-C-D-Q-E-I-K-E
εV3-3 SEQ ID NO：102 E-N-N-I-R-K-A-L-S
εV3-4 SEQ ID NO：103 G-E-V-R-Q-G-Q-A
εV5-1 SEQ ID NO：104 E-A-I-V-K-Q
εV5-2 SEQ ID NO：105 I-K-T-K-R-D-V
εV5-2.1 SEQ ID NO：106 I-K-T-K-R-L-I
Peptide SEQ ID NO. Sequence
εV5-3 SEQ ID NO：107 C-E-A-I-V-K-Q
εV5-4 SEQ ID NO：108 T-K-R-D-V-N-N-F-D-Q
ζV1-1 SEQ ID NO：109 V-R-L-K-A-H-Y
ζV1-2 SEQ ID NO：140 V-D-S-E-G-D
ζV1-3 SEQ ID NO：111 V-F-P-S-I-P-E-Q
ζV3-1 SEQ ID NO：112 S-Q-E-P-P-V-D-D-K-N-E-D-A-D-L
ζV3-2 SEQ ID NO：113 I-K-D-D-S-E-D
ζV3-3 SEQ ID NO：114 P-V-I-D-G-M-D-G-I
ζV5-1 SEQ ID NO：115 E-D-A-I-K-R
ζV5-1.1 SEQ ID NO：116 E-D-A-I-R
ζV5-2 SEQ ID NO：117 I-T-D-D-Y-G-L-D
ζV5-2.1 SEQ ID NO：118 I-T-D-D-Y-G-D-L
ζV5-3 SEQ ID NO：119 D-D-Y-G-L-D-N
ηV1-1 SEQ ID NO：120 N-G-Y-L-R-V-R
ηV1-2 SEQ ID NO：121 E-A-V-G-L-Q-P-T
ηV1-3 SEQ ID NO：122 L-A-V-F-H-E-T-P-L-G-Y
ηV1-4 SEQ ID NO：123 D-F-V-A-N-C-T-L
ηV1-5 SEQ ID NO：124 W-V-D-L-E-P-E-G-K-V
ηV1-6 SEQ ID NO：125 H-S-L-F-K-K-G-H
ηV1-7 SEQ ID NO：126 T-G-A-S-D-T-F-E-G
ηV5-1 SEQ ID NO：127 E-G-H-L-P-M
ηV5-1.1 SEQ ID NO：128 E-G-H-D-P-M
ηV5-2 SEQ ID NO：129 I-K-S-R-E-D-V-S
ηV5-3 SEQ ID NO：130 V-R-S-R-E-D-V-S
ηV5-4 SEQ ID NO：131 P-R-I-K-S-R-E-D-V
λV1-1 SEQ ID NO：132 H-Q-V-R-V-K-A-Y-Y-R
λV1-2 SEQ ID NO：133 Y-E-L-N-K-D-S-E-L-L-I
λV3-1 SEQ ID NO：134 M-D-Q-S-S-M-H-S-D-H-A-Q-T-V-I
λV3-2 SEQ ID NO：135 L-D-Q-V-G-E-E
λV3-3 SEQ ID NO：136 E-A-M-N-T-R-E-S-G
λV5-1 SEQ ID NO：137 D-D-I-V-R-K
μV5-2 SEQ ID NO：138 V-K-L-C-D-F-G-F
μV5-2.1 SEQ ID NO：139 I-R-L-C-D-F-A-F
μV5-3 SEQ ID NO：140 Q-V-K-L-C-D-F-G-F-A
μV1-1 SEQ ID NO：141 M-S-V-P-P-L-L-R-P
μV1-2 SEQ ID NO：142 K-F-P-E-C-G-F-Y-G-L-Y
μV3-1 SEQ ID NO：143 D-P-D-A-D-Q-E-D-S
μV3-2 SEQ ID NO：144 S-K-D-T-L-R-K-R-H
μV3-3 SEQ ID NO：145 I-T-L-F-Q-N-D-T-G
μV3-4 SEQ ID NO：146 G-S-N-S-H-K-D-I-S
μV5-1 SEQ ID NO：147 S-D-S-P-E-A
ΘV1-1 SEQ ID NO：148 G-L-S-N-F-D-C-G
ΘV1-2 SEQ ID NO：149 Y-V-E-S-E-N-G-Q-M-Y-I
ΘV1-3 SEQ ID NO：150 I-V-K-G-K-N-V-D-L-I
Peptide SEQ ID NO. Sequence
ΘV1-4 SEQ ID NO：151 D-M-N-E-F-E-T-E-G-F
ΘV3-1 SEQ ID NO：152 C-S-I-K-N-E-A-R-L
ΘV3-2 SEQ ID NO：153 G-K-R-E-P-Q-G-I-S
ΘV3-3 SEQ ID NO：154 D-E-V-D-K-M-C-H-L
ΘV5-1 SEQ ID NO：155 R-A-L-I-N-S
ΘV5-2 SEQ ID NO：156 V-K-S-P-F-D-C-S
ΘV5-2.1 SEQ ID NO：157 V-R-S-P-F-D-C-S
ΘV5-3 SEQ ID NO：158 D-R-A-L-I-N-S
ιV5-1 SEQ ID NO：159 I-S-G-E-F-G-L-D
ιV5-1.1 SEQ ID NO：160 C-S-G-E-F-G-L-D
ιV5-2 SEQ ID NO：161 D-D-D-I-V-R-K
ιV5-3 SEQ ID NO：162 D-D-I-V-R-K
[0030] more expound adequately as following, preferred PKC regulates peptide and transit peptides chemical association.In particularly preferred embodiments, regulating peptide is connected by disulfide bond with transit peptides.In the situation that forms disulfide bond, be added to the Cys residue on the PKC adjusting peptide sequence and be favourable, preferably be added to the aminoterminal of this peptide.Alternatively, endogenous Cys residue can be used to connect and regulate peptide and transit peptides or transport part.The method that forms disulfide bond is known those of ordinary skills, for example mixes various compositions in reducing environment, then these compositions is introduced in the oxidation environment.
Transit peptides
[0031] discovery plan is used for the multiple molecule (particularly big molecule such as peptide) of cellular uptake and is seldom transported by cross-cell membrane.Be suggested the various schemes that are used for helping cellular uptake, used the transhipment part as cation (being positively charged) polymer, peptide and antibody sequence, it comprises many lysines, pR60, feeler foot-derived peptide, HIV Tat-derived peptide etc.(referring to, for example United States Patent (USP) and announcement the 4th, 847,240,5,652,122,5,670,617,5674,980,5,747,641,5,804,604,5,888,762,6,316,003,6,593,292, US2003/0104622, US2003/0199677 and US2003/0206900 number, all these patents and disclosed full content are introduced into this paper by reference).
[0032] instantiation of peptide/transporter bond is KAI-9803 (SEQ IDNO:1), and it is made by δ PKC-derived peptide and the HIV Tat-transit peptides of deriving.It is developed the human therapeutic that is used for the treatment of reperfusion injury at present and uses.The same with the most drug activating agent, KAI-9803 be prepared as have some stability, the pharmaceutical preparation of tolerance and bioavailability requirement.
Excipient and anti-aggregating agent prepared therefrom
[0033] the pharmaceutically acceptable excipient that is suitable as carrier or thinner is being known in the art, and can be used to several formulations.Referring to, for example Remington ' s Pharmaceutical Sciences, the 18th edition, A.R.Gennaro, Editor, Mack PublishingCompany (1990); Remington:The Science and Practice of Pharmacy, the 20th edition, A.R.Gennaro, Editor, Lippincott Williams ﹠amp; Wilkins (2000); Handbook of Pharmaceutical Excipients, the 3rd edition, A.H.Kibbe, Editor, American Pharmaceutical Association and Pharmaceutical Press (2000); With Handbook of Pharmaceutical Additives, Michael and Irene Ash edit, Gower (1995).
[0034] usually, lyophilized formulations is by the activating agent preparation that is dissolved in the pharmaceutically acceptable solvent, and described solvent is chosen wantonly and comprised excipient, for example swelling agent, solubilizer, pH buffer solution etc.The temperature and pressure that the solution process reduces stays solids cake compresses piece (solid cake) to remove liquid, and it can be stored to use in the future.
[0035] lyophilized formulations of invention of the present disclosure advantageously comprises anti-aggregating agent prepared therefrom such as sugar, and wherein this class sugar hydrophobic and/or positively charged part enough and activating agent interacts so that they organize structure with described sugar, rather than assembles each other.Suitable anti-aggregating agent prepared therefrom steamed bun stuffed with sugar is drawn together fructose, lactose, glycerine, mannitol and D-mannose, preferred mannitol.
[0036] with the transhipment part of helping cellular uptake peptide (for example δ PKC sequence part of KAI-9803), own some characteristic (normally cationic) together, these characteristics facilitate their body interior functional, but have found that these characteristics cause forming aggregation under the condition of storage of freeze-drying.Regulate peptide and also can have the architectural feature that promotes that aggregation forms.Although do not wish to be fettered by any concrete theory, this gathering may be become with peptide " group structure " due to the tendentiousness of aggregation by the peptide dimerization.
[0037] dissolving again of peptide and peptide bond is disturbed in the formation of the aggregation of harmful level, and it disturbs particulate again may be the administration of unacceptable some method of administration (for example administration in the hat).Although these shortcomings, the generation of the aggregation of harmful level makes the ultimate density of the accurate amount of the peptide that dissolves in definite per unit liquid become complicated in preparation.Do not determine initial, deduct then under the situation of the weight of dissolved substance not, thisly determine and accurately to be calculated.The unacceptable level that pf assembles can cause the gathering of peptide bond 0.1 to 50%.Therefore, another aspect of the present invention mixes in the lyophilized formulations of multiple peptide or peptide/transporter bond about resisting aggregating agent prepared therefrom.Except suppress the formation of aggregation in lyophilized products, some anti-aggregating agent prepared therefrom can strengthen the stabilization of pharmaceutical preparation.
Administration
[0038] parenteral is usually expressed as injection, in subcutaneous, intramuscular, the peritonaeum, intravenous injection, under situation of the present invention through injecting in the hat.Injectable drug can prepare with traditional form, reconstitutes solid (for example drying or the freeze-drying) form of solution or suspension as liquid solution or suspension, before being suitable for injecting or as emulsion in liquid.Generally speaking, the excipient of Shi Heing comprises for example water, salt solution, glucose, glycerine, ethanol or analog.In addition, can use the non-toxic auxiliary substances of minor amount, for example wetting agent or emulsifier, pH buffer, solubilizer, tonicifier and analog comprise for example sodium acetate, sorbitan mono-laurate, triethanolamine oleate (salt), cyclodextrin etc.Being used for formulation that intravenous (IV) uses generally comprises and is incorporated into simple chemicals---as sugar, amino acid or electrolyte---the activating agent of sterile solution, it is recycled system easily and carries and absorb.This class solution is generally with salt solution or buffer preparation.The pH of this class IV fluid can change, and is generally 3.5 to 8.0, as known in the art.
[0039] ejection preparation generally uses sodium chloride for injection in the hat of disclosure invention, and it is 0.001 to 2.5mg/mL that USP (preferred 0.9%) reconstitutes concentration with the API of freeze-drying, preferred 0.01 to 1.0mg/mL solution and preparing.
Exemplary formulation
[0040] pharmaceutical preparation of invention of the present disclosure preferably includes PKC and regulates peptide, transit peptides and anti-aggregating agent prepared therefrom.Usually, PKC regulates peptide and transit peptides by chemical association each other.For example, preferably, regulate peptide and transit peptides quilt covalent bond each other, in preferred embodiment, PKC regulates peptide and is connected by disulfide bond with transit peptides.
[0041] in the embodiment of the pre-freeze-drying of the present invention, preparation comprises that further (preferred water for injection is USP) to dissolve aforementioned composition for the pharmaceutically acceptable solvent of q.s.The embodiment of freeze-drying of the present invention comprises the mentioned component of solids cake compresses piece form.
[0042] in preparation of the present disclosure the proportion of peptide and anti-aggregating agent prepared therefrom from about 100: 1 to about 5: 1, preferably from about 80: 1 to about 5: 1, more preferably from about 80: 1 to about 8: 1, actual ratio will depend on the characteristic (identity) of various compositions and the concentration of drug products freeze-drying and/or reconstruct expectation.
[0043] one aspect of the present invention provides the pre-lyophilized formulations of peptide or peptide/transporter bond and from its lyophilized products that obtains, it is as follows:
Table 2
Composition Amount (wt/vol (weight per volume))
API 0.25 to 5.0mg/mL
The anti-sugar of assembling 2.0 to 50.0mg/mL
WFI(USP) Supply (q.s.) to 100
[0044] another aspect of preferred peptide or peptide/transporter conjugate preparations can obtain by the freeze-drying following ingredients:
Table 3
Composition Amount (wt/vol)
API 0.1 to 10.0mg/mL
The anti-sugar of assembling 5.0 to 40.0mg/mL
WFI(USP) Complement to 100
[0045] preferred peptide or peptide/transporter conjugate preparations can obtain by the freeze-drying following ingredients:
Table 4
Composition Amount (wt/vol)
API 2.0 to 3.0mg/mL
The anti-sugar of assembling 15.0 to 25.0mg/mL
WFI(USP) Complement to 100
[0046] another preferred peptide or peptide/transporter conjugate preparations can obtain by the freeze-drying following ingredients:
Table 5
Composition Amount (wt/vol)
API 0.5 to 5.0mg/mL
The anti-sugar of assembling 10.0 to 30.0mg/mL
WFI(USP) Complement to 100
[0047] another preferred peptide or peptide/transporter conjugate preparations can obtain by the freeze-drying of following ingredients:
Table 6
Composition Amount (wt/vol)
API 2.0 to 3.0mg/mL
The anti-sugar of assembling 15.0 to 25.0mg/mL
WFI(USP) Complement to 100
[0048] further preferred peptide or peptide/transporter conjugate preparations can obtain by the freeze-drying of following ingredients:
Table 7
Composition Quantity
KAI-9803 5.0mg
Mannitol (USP) 40.0mg
WFI(USP) 2.0mL
[0049] alternatively, KAI-9803 water-based parenteral solution can be prepared into and be substantially free of sugar, and concentration range is about 0.01 to about 10.0mg/mL, is preferably about 0.1 to about 5.0mg/mL, more preferably about 0.1 to about 1.0mg/mL.The pH of this aqueous solution is adjusted between about 0.2 to 4.0, preferably between about 2.5 to 3.5.
The method of making and using
[0050] PKC adjusting peptide and transit peptides can be synthetic according to tradition (for example solid phase) method.Activate PKC regulate on one of them of peptide and transit peptides Cys (for example, use 2,2 '-two thiobis (5-nitro-pyrimidine) activated carrier peptide) afterwards, with two kinds of peptide couplings, separate, purifying [for example, uses the acetonitrile wash-out in TEAP buffer solution (triethylamine and phosphoric acid) then, RP-HPLC carries out purifying by the preparation type, produces the phosphate of purifying].Then, collect the fraction of the peptide that contains purifying and coupling that obtains from HPLC.By repeating RP-HPLC, can exchange pharmaceutically acceptable salt with acetonitrile and the organic or inorganic acid balance ion donor that needs (as acetate, hydrochloric acid, tartaric acid etc., preferred acetate) wash-out.The end-product that collect to need divides the freeze drying bottle of packing into, freeze-drying, and transferring to the suitable vessel that is used for storing (preferably the temperature of reduction as-20 ℃ under be transferred in the pale brown look glass container of sealing) before the preparation.
[0051] equilibrium ion that uses at the production period of KAI-9803 has active influence to dissolubility and stability.In preferred embodiment, use acetate (ester) equilibrium ion.Also consider other equilibrium ion, as the chloride equilibrium ion.Although using acetate (ester) equilibrium ion is the preferred implementation of disclosure invention, it not necessarily.
[0052] pharmaceutical preparation of the present invention can be according to the most received practice manufacturing, and is for example, as described below:
(a) anti-aggregating agent prepared therefrom, hydrophobic active agent and/or the cation transfer part of appropriate amount are introduced the suitably container (preferred glass bottle) of size as drying solid.
(b) amount of pharmaceutically acceptable solvent [for example water for injection (" WFI ")] with enough dissolved solids and acquisition expectation concentration joined in the described container.
The solution that (c) will so form filters, aseptic being dispensed in the pre-sterilized container, and freeze drying.
(d) with seal of vessel (randomly after at first for example nitrogen is filled head space with non-active gas), store up to reconstruct to carry out administration.
[0053] recommend this class drug products to be stored in room temperature or below the room temperature, preferably at approximately 2-8 ℃ (more preferably at 5 ℃), its specification should be illustrated in label, its external packing of container or its adhesion and any packing insert of wherein containing on.
[0054] for the reconstruct lyophilized formulations carries out administration, this product at first was warming up to about room temperature before opening.A moment before use is by entering the container of sealing with pin by rubber stopper, with enough dissolving lyophilized cake pieces and provide the amount of the administration concentration of expectation to add pharmaceutically acceptable solvent (such as salt solution, preferred 9% salt solution).Can be provided at this reconstruct specification in the Arzneibucs, on the dosage card, perhaps it can be incorporated on label, external packing and/or the packing insert of container or its adhesion.
Detect
[0055] can finish detection by means commonly known in the art to pharmaceutical preparation of the present invention, comprise: for example before or after freeze-drying and reconstruct, determine the characteristic and the concentration of active pharmaceutical ingredient by HPLC-UV (measure 206,220 and/or the absorbance at 280nm place); Determine the water content in the lyophilized products; The pH of pre-freeze-drying solution and reconstituted solutions; Outward appearance with the lyophilized cake piece.
Embodiment
[0056] the following examples are used for describing the mode of using foregoing invention more fully, and are used to set forth the best mode that enforcement various aspects of the present invention are considered.Should be appreciated that these embodiment are never as restriction true scope of the present invention, but proposition is used for illustrative purpose.The full content of all lists of references that this paper quotes is introduced into by reference.
Embodiment 1
The manufacturing of KAI-9803 acetate
A. fragments of peptides is synthetic
[0057] with Merrifield resin pre-expansion at least two hours in carrene (DCM).Drain DCM.Transporter and δ-PKC peptide prepares by solid phase synthesis, and is as described below:
1. go protection (TFA/DCM),
2. resin washing (2-propyl alcohol, methyl alcohol, 10%TEA/DCM, methyl alcohol and DCM)
The next amino acid residue of coupling (t-Boc-AA-OH uses HOBt/HBTU/NMM) and
4. resin washing (methyl alcohol and DCM).
[0058] detect by carrying out ninhydrine, protection and coupling are gone in monitoring.After each peptide (Cys) is gone up the last amino acid residue of introducing, make resin peptide go protection and washing (above-mentioned steps 1,2 and 4).Peptide-resin key and side chain protected group cut by handling with the HF/ methyl phenyl ethers anisole, and pass through ether sedimentation.
B. the fragments of peptides purifying with separate
[0059] acetonitrile gradient in the use trifluoroacetic acid solution will be prepared type RP-HPLC as transporter and the δ-PKC peptide that obtains in embodiment 1A on the C-18 post.The standard of accepting of these intermediate peptide purity is not less than 90.0%.
C. coupling
[0060] by with 2,2 '-two thiobis (5-nitro-pyrimidine) contacts, with the transit peptides that obtains---for example, described in embodiment 1B---activate, contact with δ-PKC peptide then, to obtain the peptide bond KAI-9803 of coupling from embodiment 1B.
D. purifying, salt exchange and separate
[0061] use acetonitrile eluent in the TEAP buffer solution (triethylamine and phosphoric acid), by preparation type RP-HPLC, purifying is as at the thick KAI-9803 that obtains described in the embodiment 1C on the YMCC-18 post.Carry out middle method (in-process method) by analytic type RP-HPLC, analyze the fraction that produces by purifying.Those fractions of purity rubric (being not less than 95%) are satisfied in collection, it are loaded back on the same C-18 post, with the acetonitrile wash-out in the acetate buffer, to produce corresponding KAI-9803 acetate.Collect the KAI-9803 acetate of purifying like this, divide the freeze drying bottle and freezing of packing into.The bottle that this is freezing is connected on the freeze-drying instrument concetrated pipe (lyophilizermanifold), and implements freeze-drying.After finishing freeze-drying, the KAI-9803 acetate powder of weighing gained, sampling detects, and residue is transferred in the pale brown look glass container of 50mL.With plug (snap-on stopper) closed container of 20mm (grey) butyl (rubber), band snap-on, and be stored in-20 ℃.
Embodiment 2
Preparation, freeze-drying, fill and finish
[0062] will be dissolved among the WFI of about 14.0mL as describing the KAI-9803 acetate powder (50.0mg) and the mannitol USP (400.0mg) that obtain at example I D, add WFI 20ml (approximately 6ml) extremely altogether then when needed, to produce transparent colourless solution.Detect the complete dissolubility of confirming transparency, color and solid by naked eyes.By two 0.22 continuous μ m filters solution is aseptically filled in 100 grades the aseptic pad device (class 100 asepticfilling suite).In aseptic each that is dispensed in 10 pre-sterilized 20mL bottles of solution with the 2ml filtration.Thrust each bottle with the freeze-drying of trough of belt and add a cover, and with it as for being chilled in advance on-50 ℃ the shelf.Under 5 ℃ of shelf temperatures, implement elementary drying cycles, it is no less than 20 hours, under 25 ℃ of shelf temperatures, implements secondary drying cycles then, and it is no less than 3 hours.After finishing freeze-drying circulation, clog bottle having under the nitrogen of partial vacuum, and sealing.The bottle that clogs is curled and in 10,000 grades of treatment facilities (processing suit), check.Give bottle labelled, move on to storage under the 2-8 ℃ of isolation (quarantine) then.
Embodiment 3
The reconstruct of KAI-9803+ mannitol formulations
[0063] contain 5mg KAI-9803 and 40mg mannitol freeze-dried pharmaceutical formulation bottle (for example, obtain as in embodiment 1 and 2, describing) by inject the adding 20mL 0.9% sodium chloride for injection, USP, the rotation by gentleness makes the inclusion dissolving, to produce transparent solution.Add 18mL 0.9% sodium chloride for injection in aseptic, empty IV bag, USP adds 2mL KAI-9803 solution (obtaining) then from bottle, is the 0.1mg/mL KAI-9803 solution of 20mL to produce cumulative volume in the IV bag.This solution is stored at room temperature, and use in after preparation 4 hours.
Embodiment 4
Freeze-drying KAI-9803 stability of formulation
[0064] for example as preparation KAI-9803 preparation as described in embodiment 1 and 2, it uses mannitol and replaces mannitol with fructose and sucrose assembles the preparation procedure that sugar carries out embodiment 2 as resisting.Detect the complete dissolubility of transparency, color and the solid of all solution by naked eyes, from each solution, shift out aliquot (aliquot).Use HLPC-UV to analyze each aliquot KAI-9803 concentration, measure 206 and the absorbance at 280nm place.With rest solution filtration, filling, freeze-drying and finish, as in embodiment 2, describing.Separate one group of bottle representing each preparation, be reconstructed and check (HPLC-UV is in 206/280nm) at once to determine the KAI-9803 concentration in the reconstruct product.Remaining bottle is divided into several groups, is used for storing down in the temperature (for example 35 ℃) of temperature (for example 2-8 ℃), room temperature and the rising of lowering.Represent the bottle of respectively organizing of each preparation to fetch (for example 1 day, 1 week, January, March, June) at selected time point, with its reconstruct, naked eyes detect and the concentration (HPLC-UV is in 206/280nm) of check KAI-9803.
Embodiment 5
The KAI-9803 preparation is to the influence of CK release and infarct size
[0065] male SD rat of 250g (Sprague Dawley rat) is anaesthetized by the yellow Jackets of intraperitoneal injection 1ml 5.2%.After confirming to the reaction of pain shortage, shift out heart, and in being cooled to Kreb-Henslitt buffer solution about 4 ℃, that lack calcium or glucose, and by sustainer insertion sleeve pipe.Sleeve pipe is connected to reverse Langendorff instrument, and the Krebs-Henslitt buffer solution that contains calcium and glucose that is heated to 37 ℃ is there gone into (10ml/ minute) heart by reverse perfusion.
[0066] heart was stablized 10 minutes.Then, by stopping to make 30 minutes temperature (type) global ischemia of heart experience to heart perfusion and in the Krebs-Henslitt of temperature control buffering bath of liquid, soaking heart under 37-38 ℃.After 30 minutes ischemic stage, perfused hearts again.Working concentration is the test compound dosage range of 50pM, 500pM, 5nM, 50nM and 500nM.Dose concentration has reacted the ultimate density of trial target in the buffer solution.
[0067] Krebs-Henslitt buffer solution:
0.1256M the 2.512M stoste (stock) of NaCl-50ml is to 1L
0.02475M NaHCO 3The 0.495M stoste of-50ml is to 1L
0.00475M the 0.475M stoste of KCl-10ml is to 1L
0.00118M MgSO 4The 0.118M stoste of-10ml is to 1L
0.00118M KH 2PO 4The 0.118M stoste of-10ml is to 1L
5mM glucose-0.9g/L
0.002M CaCl 2The 0.25M stoste of-8ml is to 1L
Transfer pH to 7.4 with 1M HCl.
[0068] select terminal point with the influence of monitoring specifically to tissue damage.Because the restriction of equipment, the pressure that functional terminal point such as left ventricle form does not have selected.The reperfusion injury measured value in tissue damage terminal point and all other past is relevant all the time.
Creatine kinase (CK) discharges
[0069] in whole perfusion again with 2.5 minutes interval, collect the perfusion liquid fraction.Analyze the creatine kinase activity of each fraction, as use 96 hole ELISA plate readers by CK kinases kit (Diagnostic Chemicals Limited; Oxford CT) determines.The result who analyzes is shown in Fig. 2 and Fig. 3.Increase KAI-9803 concentration and reduced total creatine kinase release.
Infarct size:
[0070] after pouring into again, heart level is cut into 3-4 section.Then, under 39 ℃, in salt solution chlorinated triphenyl base-tetrazolium () of 2% (TTC) in, to heart dyeing 2.5 minutes.Organize the infraction percentage of area in the digital picture based on the weight of heart section and the heart that dyes, infarct size is quantized.Be used to calculate infarct size from the 3rd section at heart top.Use digital picture, determine infarct size % by the surface area measured value among the Photoshop.Fig. 4 illustrates typical results.
Sequence table
＜110〉Kai Medicament Ltd.
Lee MT
＜120〉pharmaceutical preparation
<130>578422000140
＜140〉do not provide as yet
＜141〉meanwhile
<150>11/240,962
<151>2005-09-30
<160>173
<170>FastSEQ for Windows Version 4.0
<210>1
<211>23
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>1
Cys Ser Phe Asn Ser Tyr Glu Leu Gly Ser Leu Cys Tyr Gly Arg Lys
1 5 10 15
Lys Arg Arg Gln Arg Arg Arg
20
<210>2
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>2
Ile Pro Glu Gly Asp Glu Glu Gly
1 5
<210>3
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>3
Gln Leu ValIle Ala Asn
1 5
<210>4
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>4
Gly Leu Gly Ala Glu Asn
1 5
<210>5
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>5
Ala Arg Gly Ala Glu Asn
1 5
<210>6
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>6
Cys Gly Lys Gly Ala Glu Asn
1 5
<210>7
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>7
Cys Gly Lys Gly Ala Glu Asn
1 5
<210>8
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>8
Lys Gln Lys Thr Lys Thr Ile Lys
1 5
<210>9
<211>13
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>9
Met Asp Pro Asn Gly Leu Ser Asp Pro Tyr Val Lys Leu
1 5 10
<210>10
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>10
Ile Pro Asp Pro Lys Ser Glu
1 5
<210>11
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>11
Ser Leu Asn Pro Glu Trp Asn Glu Thr
1 5
<210>12
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>12
Val Pro Pro Glu Gly Ser Glu Ala
1 5
<210>13
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>13
Lys Leu Phe Ile Met Asn
1 5
<210>14
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>14
Arg Asp Lys Arg Asp Thr Ser
1 5
<210>15
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>15
Cys Ala Arg Asp Lys Arg Asp Thr Ser
1 5
<210>16
<211>8.
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>16
Gly Arg Asp Lys Arg Asp Thr Ser
1 5
<210>17
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>17
Ala Arg Asp Lys Arg Asp Thr Ser
1 5
<210>18
<211>12
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>18
Ala Arg Asp Lys Arg Asp Thr Ser Asn Phe Asp Lys
1 5 10
<210>19
<211>14
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>19
Ala Gly Phe Ser Tyr Thr Asn Pro Glu Phe Val Ile Asn Val
1 5 10
<210>20
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>20
Gln Glu Val Ile Arg Asn
1 5
<210>21
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>21
Cys Gly Arg Asn Ala Glu
1 5
<210>22
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>22
Ala Cys Gly Arg Asn Ala Glu
1 5
<210>23
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>23
Ala Cys Gly Lys Asn Ala Glu
1 5
<210>24
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>24
Lys Ala Cys Gly Arg Asn Ala Glu
1 5
<210>25
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>25
Cys Gly Arg Asn Ala Glu Asn
1 5
<210>26
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>26
Ala Cys Gly Arg Asn Ala Glu
1 5
<210>27
<211>14
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>27
Ser Phe Val Asn Ser Glu Phe Leu Lys Pro Glu Val Leu Ser
1 5 10
<210>28
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>28
Val Ala Asp Ala Asp Asn Cys Ser
1 5
<210>29
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>29
Gly Arg Ser Gly Glu Asn
1 5
<210>30
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>30
Gly Leu Ser Gly Glu Asn
1 5
<210>31
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>31
Arg Leu Val Leu Ala Ser
1 5
<210>32
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>32
Pro Cys Gly Arg Ser Gly Glu Asn
1 5
<210>33
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>33
Cys Ser Phe Asn Ser Tyr Glu Leu Gly Ser Leu
1 5 10
<210>34
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>34
Ser Phe Asn Ser Tyr Glu Leu Gly Ser Leu
1 5 10
<210>35
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>35
Thr Phe Asn Ser Tyr Glu Leu Gly Ser Leu
1 5 10
<210>36
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>36
Ala Phe Asn Ser Asn Tyr Glu Leu Gly Ser Leu
1 5 10
<210>37
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>37
Ser Phe Asn Ser Tyr Glu Leu Gly Thr Leu
1 5 10
<210>38
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>38
Ser Thr Asn Ser Tyr Glu Leu Gly Ser Leu
1 5 10
<210>39
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>39
Ser Phe Asn Ser Phe Glu Leu Gly Ser Leu
1 5 10
<210>40
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>40
Ser Asn Ser Tyr Asp Leu Gly Ser Leu
1 5
<210>41
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>41
Ser Phe Asn Ser Tyr Glu Leu Pro Ser Leu
1 5 10
<210>42
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>42
Thr Phe Asn Ser Tyr Glu Leu Gly Thr Leu
1 5 10
<210>43
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>43
Ser Phe Asn Ser Tyr Glu Ile Gly Ser Val
1 5 10
<210>44
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>44
Ser Phe Asn Ser Tyr Glu Val Gly Ser Ile
1 5 10
<210>45
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>45
Ser Phe Asn Ser Tyr Glu Leu Gly Ser Val
1 5 10
<210>46
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>46
Ser Phe Asn Ser Tyr Glu Leu Gly Ser Ile
1 5 10
<210>47
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>47
Ser Phe Asn Ser Tyr Glu Ile Gly Ser Leu
1 5 10
<210>48
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>48
Ser Phe Asn Ser Tyr Glu Val Gly Ser Leu
1 5 10
<210>49
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>49
Ala Phe Asn Ser Tyr Glu Leu Gly Ser Leu
1 5 10
<210>50
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>50
Tyr Asp Leu Gly Ser Leu
1 5
<210>51
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>51
Phe Asp Leu Gly Ser Leu
15
<210>52
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>52
TyrAspIle Gly Ser Leu
15
<210>53
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>53
Tyr Asp Val Gly Ser Leu
1 5
<210>54
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>54
Tyr Asp Leu Pro Ser Leu
1 5
<210>55
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>55
Tyr Asp Leu Gly Leu Leu
1 5
<210>56
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>56
Tyr Asp Leu Gly Ser Ile
1 5
<210>57
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>57
Tyr Asp Leu Gly Ser Val
1 5
<210>58
<211>4
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>58
Ile Gly Ser Leu
1
<210>59
<211>4
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>59
Val Gly Ser Leu
1
<210>60
<211>4
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>60
Leu Pro Ser Leu
1
<210>61
<211>4
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>61
Leu Gly Leu Leu
1
<210>62
<211>4
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>62
Leu Gly Ser Ile
1
<210>63
<211>4
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>63
Leu Gly Ser Val
1
<210>64
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>64
Ala Leu Ser Thr Glu Arg Gly Lys Thr Leu Val
1 5 10
<210>65
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>65
Ala Leu Ser Thr Asp Arg Gly Lys Thr Leu Val
1 5 10
<210>66
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>66
Ala Leu Thr Ser Asp Arg Gly Lys Thr Leu Val
1 5 10
<210>67
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>67
Ala Leu Thr Thr Asp Arg Gly Lys Ser Leu Val
1 5 10
<210>68
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>68
Ala Leu Thr Thr Asp Arg Pro Lys Thr Leu Val
1 5 10
<210>69
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>69
Ala Leu Thr Thr Asp Arg Gly Arg Thr Leu Val
1 5 10
<210>70
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>70
Ala Leu Thr Thr Asp Lys Gly Lys Thr Leu Val
1 5 10
<210>71
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>71
Ala Leu Thr Thr Asp Lys Gly Lys Thr Leu Val
1 5 10
<210>72
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>72
Val Leu Met Arg Ala Ala Glu Glu Pro Val
1 5 10
<210>73
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>73
Gln Ser Met Arg Ser Glu Asp Glu Ala Lys
1 5 10
<210>74
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>74
Gln Gly Phe Glu Lys Lys Thr Gly Val
1 5
<210>75
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>75
Asp Asn Asn Gly Thr Tyr Gly Lys Ile
1 5
<210>76
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>76
Lys Asn Leu Ile Asp Ser
1 5
<210>77
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>77
Val Lys Ser Pro Arg Asp Tyr Ser
1 5
<210>78
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>78
Val Lys Ser Pro Cys Arg Asp Tyr Ser
1 5
<210>79
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>79
Ile Lys Ser Pro Arg Leu Tyr Ser
1 5
<210>80
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>80
Lys Asn Leu Ile Asp Ser
1 5
<210>81
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>81
Pro Lys Val Lys Ser Pro Arg Asp Tyr Ser Asn
1 5 10
<210>82
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>82
Asn Gly Leu Leu Lys Ile Lys
1 5
<210>83
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>83
Glu Ala Val Ser Leu Lys Pro Thr
1 5
<210>84
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>84
Leu Ala Val Phe His Asp Ala Pro Ile Gly Tyr
1 5 10
<210>85
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>85
Asp Asp Phe Val Ala Asn Cys Thr Ile
1 5
<210>86
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>86
Trp Ile Asp Leu Glu Pro Glu Gly Arg Val
1 5 10
<210>87
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>87
His Ala Val Gly Pro Arg Pro Gln Thr Phe
1 5 10
<210>88
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>88
Asn Gly Ser Arg His Phe Glu Asp
1 5
<210>89
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>89
His Asp Ala Pro Ile Gly Asp Tyr
1 5
<210>90
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>90
His Asp Ala Pro Ile Gly
1 5
<210>91
<211>8.
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>91
His Asp Ala Ala Ile Gly Tyr Asp
1 5
<210>92
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>92
His Asp Ala Pro Ile Pro Tyr Asp
1 5
<210>93
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>93
His Asn Ala Pro Ile Gly Tyr Asp
1 5
<210>94
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>94
His Ala Ala Pro Ile Gly Tyr Asp
1 5
<210>95
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>95
Ala Asp Ala Pro Ile Gly Tyr Asp
1 5
<210>96
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>96
His Asp Ala Pro Ala Gly Tyr Asp
1 5
<210>97
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>97
His Asp Ala Pro Ile Gly Ala Asp
1 5
<210>98
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>98
His Asp Ala Pro Ile Ala Tyr Asp
1 5
<210>99
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>99
His Asp Ala Pro Ile Gly Tyr Ala
1 5
<210>100
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>100
Ser Ser Pro Ser Glu Glu Asp Arg Ser
1 5
<210>101
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>101
Pro Cys Asp Gln Glu Ile Lys Glu
1 5
<210>102
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>102
Glu Asn Asn Ile Arg Lys Ala Leu Ser
1 5
<210>103
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>103
Gly Glu Val Arg Gln Gly Gln Ala
1 5
<210>104
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>104
Glu Ala Ile Val Lys Gln
1 5
<210>105
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>105
Ile Lys Thr Lys Arg Asp Val
1 5
<210>106
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>106
Ile Lys Thr Lys Arg Leu Ile
1 5
<210>107
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>107
Cys Glu Ala Ile Val Lys Gln
1 5
<210>108
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>108
Thr Lys Arg Asp Val Asn Asn Phe Asp Gln
1 5 10
<210>109
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>109
Val Arg Leu Lys Ala His Tyr
1 5
<210>110
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>110
Val Asp Ser Glu Gly Asp
1 5
<210>111
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>111
Val Phe Pro Ser Ile Pro Glu Gln
1 5
<210>112
<211>15
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>112
Ser Gln Glu Pro Pro Val Asp Asp Lys Asn Glu Asp Ala Asp Leu
1 5 10 15
<210>113
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>113
Ile Lys Asp Asp Ser Glu Asp
1 5
<210>114
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>114
Pro Val Ile Asp Gly Met Asp Gly Ile
1 5
<210>115
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>115
Glu Asp Ala Ile Lys Arg
1 5
<210>116
<211>5.
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>116
Glu Asp Ala Ile Arg
1 5
<210>117
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>117
Ile Thr Asp Asp Tyr Gly Leu Asp
1 5
<210>118
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>118
Ile Thr Asp Asp Tyr Gly Asp Leu
1 5
<210>119
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>119
Asp Asp Tyr Gly Leu Asp Asn
1 5
<210>120
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>120
Asn Gly Tyr Leu Arg Val Arg
1 5
<210>121
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>121
Glu Ala Val Gly Leu Gln Pro Thr
1 5
<210>122
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>122
Leu Ala Val Phe His Glu Thr Pro Leu Gly Tyr
1 5 10
<210>123
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>123
Asp Phe Val Ala Asn Cys Thr Leu
1 5
<210>124
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>124
Trp Val Asp Leu Glu Pro Glu Gly Lys Val
1 5 10
<210>125
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>125
His Ser Leu Phe Lys Lys Gly His
1 5
<210>126
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>126
Thr Gly Ala Ser Asp Thr Phe Glu Gly
1 5
<210>127
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>127
Glu Gly His Leu Pro Met
1 5
<210>128
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>128
Glu Gly His Asp Pro Met
1 5
<210>129
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>129
Ile Lys Ser Arg Glu Asp Val Ser
1 5
<210>130
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>130
Val Arg Ser Arg Glu Asp Val Ser
1 5
<210>131
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>131
Pro Arg Ile Lys Ser Arg Glu Asp Val
1 5
<210>132
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>132
His Gln Val Arg Val Lys Ala Tyr Tyr Arg
1 5 10
<210>133
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>133
Tyr Glu Leu Asn Lys Asp Ser Glu Leu Leu Ile
1 5 10
<210>134
<211>15
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>134
Met Asp Gln Ser Ser Met His Ser Asp His Ala Gln Thr Val Ile
1 5 10 15
<210>135
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>135
Leu Asp Gln Val Gly Glu Glu
1 5
<210>136
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>136
Glu Ala Met Asn Thr Arg Glu Ser Gly
1 5
<210>137
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>137
Asp Asp Ile Val Arg Lys
1 5
<210>138
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>138
Val Lys Leu Cys Asp Phe Gly Phe
1 5
<210>139
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>139
Ile Arg Leu Cys Asp Phe Ala Phe
1 5
<210>140
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>140
Gln Val Lys Leu Cys Asp Phe Gly Phe Ala
1 5 10
<210>141
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>141
Met Ser Val Pro Pro Leu Leu Arg Pro
1 5
<210>142
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>142
Lys Phe Pro Glu Cys Gly phe Tyr Gly Leu Tyr
1 5 10
<210>143
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>143
Asp Pro Asp Ala Asp Gln Glu Asp Ser
1 5
<210>144
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>144
Ser Lys Asp Thr Leu Arg Lys Arg His
1 5
<210>145
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>145
Ile Thr Leu Phe Gln Asn Asp Thr Gly
1 5
<210>146
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>146
Gly Ser Asn Ser His Lys Asp Ile Ser
1 5
<210>147
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>147
Ser Asp Ser Pro Glu Ala
1 5
<210>148
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>148
Gly Leu Ser Asn Phe Asp Cys Gly
1 5
<210>149
<211>11
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>149
Tyr Val Glu Ser Glu Asn Gly Gln Met Tyr Ile
1 5 10
<210>150
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>150
Ile Val Lys Gly Lys Asn Val Asp Leu Ile
1 5 10
<210>151
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>151
Asp Met Asn Glu Phe Glu Thr Glu Gly Phe
1 5 10
<210>152
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>152
Cys Ser Ile Lys Asn Glu Ala Arg Leu
1 5
<210>153
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>153
Gly Lys Arg Glu Pro Gln Gly Ile Ser
1 5
<210>154
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>154
Asp Glu Val Asp Lys Met Cys His Leu
1 5
<210>155
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>155
Arg Ala Leu Ile Asn Ser
1 5
<210>156
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>156
Val Lys Ser Pro Phe Asp Cys Ser
1 5
<210>157
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>157
Val Arg Ser Pro Phe Asp Cys Ser
1 5
<210>158
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>158
Asp Arg Ala Leu Ile Asn Ser
1 5
<210>159
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>159
Ile Ser Gly Glu Phe Gly Leu Asp
1 5
<210>160
<211>8
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>160
Cys Ser Gly Glu Phe Gly Leu Asp
1 5
<210>161
<211>7.
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>161
Asp Asp Asp Ile Val Arg Lys
1 5
<210>162
<211>6
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>162
Asp Asp Ile Val Arg Lys
1 5
<210>163
<211>9
<212>PRT
＜213〉artificial sequence
<220>
＜223〉PKC regulates peptide
<400>163
Ala Phe Asn Ser Tyr Glu Leu Gly Ser
1 5
<210>164
<211>672
<212>PRT
＜213〉people (Homo sapiens)
<400>164
Met Ala Asp Val Phe Pro Gly Asn Asp Ser Thr Ala Ser Gln Asp Val
1 5 10 15
Ala Asn Arg Phe Ala Arg Lys Gly Ala Leu Arg Gln Lys Asn Val His
20 25 30
Glu Val Lys Asp His Lys Phe Ile Ala Arg Phe Phe Lys Gln Pro Thr
35 40 45
Phe Cys Ser His Cys Thr Asp Phe Ile Trp Gly Phe Gly Lys Gln Gly
50 55 60
Phe Gln Cys Gln Val Cys Cys Phe Val Val His Lys Arg Cys His Glu
65 70 75 80
Phe Val Thr Phe Ser Cys Pro Gly Ala Asp Lys Gly Pro Asp Thr Asp
85 90 95
Asp Pro Arg Ser Lys His Lys Phe Lys Ile His Thr Tyr Gly Ser Pro
100 105 110
Thr Phe Cys Asp His Cys Gly Ser Leu Leu Tyr Gly Leu Ile His Gln
115 120 125
Gly Met Lys Cys Asp Thr Cys Asp Met Asn Val His Lys Gln Cys Val
130 135 140
Ile Asn Val Pro Ser Leu Cys Gly Met Asp His Thr Glu Lys Arg Gly
145 150 155 160
Arg Ile Tyr Leu Lys Ala Glu Val Ala Asp Glu Lys Leu His Val Thr
165 170 175
Val Arg Asp Ala Lys Asn Leu Ile Pro Met Asp Pro Asn Gly Leu Ser
180 185 190
Asp Pro Tyr Val Lys Leu Lys Leu Ile Pro Asp Pro Lys Asn Glu Ser
195 200 205
Lys Gln Lys Thr Lys Thr Ile Arg Ser Thr Leu Asn Pro Gln Trp Asn
210 215 220
Glu Ser Phe Thr Phe Lys Leu Lys Pro Ser Asp Lys Asp Arg Arg Leu
225 230 235 240
Ser Val Glu Ile Trp Asp Trp Asp Arg Thr Thr Arg Asn Asp Phe Met
245 250 255
Gly Ser Leu Ser Phe Gly Val Ser Glu Leu Met Lys Met Pro Ala Ser
260 265 270
Gly Trp Tyr Lys Leu Leu Asn Gln Glu Glu Gly Glu Tyr Tyr Asn Val
275 280 285
Pro Ile Pro Glu Gly Asp Glu Glu Gly Asn Met Glu Leu Arg Gln Lys
290 295 300
Phe Glu Lys Ala Lys Leu Gly Pro Ala Gly Asn Lys Val Ile Ser Pro
305 310 315 320
Ser Glu Asp Arg Lys Gln Pro Ser Asn Asn Leu Asp Arg Val Lys Leu
325 330 335
Thr Asp Phe Asn Phe Leu Met Val Leu Gly Lys Gly Ser Phe Gly Lys
340 345 350
Val Met Leu Ala Asp Arg Lys Gly Thr Glu Glu Leu Tyr Ala Ile Lys
355 360 365
Ile Leu Lys Lys Asp Val Val Ile Gln Asp Asp Asp Val Glu Cys Thr
370 375 380
Met Val Glu Lys Arg Val Leu Ala Leu Leu Asp Lys Pro Pro Phe Leu
385 390 395 400
Thr Gln Leu His Ser Cys Phe Gln Thr Val Asp Arg Leu Tyr Phe Val
405 410 415
Met Glu Tyr Val Asn Gly Gly Asp Leu Met Tyr His Ile Gln Gln Val
420 425 430
Gly Lys Phe Lys Glu Pro Gln Ala Val Phe Tyr Ala Ala Glu Ile Ser
435 440 445
Ile Gly Leu Phe Phe Leu His Lys Arg Gly Ile Ile Tyr Arg Asp Leu
450 455 460
Lys Leu Asp Asn Val Met Leu Asp Ser Glu Gly His Ile Lys Ile Ala
465 470 475 480
Asp Phe Gly Met Cys Lys Glu His Met Met Asp Gly Val Thr Thr Arg
485 490 495
Thr Phe Cys Gly Thr Pro Asp Tyr Ile Ala Pro Glu Ile Ile Ala Tyr
500 505 510
Gln Pro Tyr Gly Lys Ser Val Asp Trp Trp Ala Tyr Gly Val Leu Leu
515 520 525
Tyr Glu Met Leu Ala Gly Gln Pro Pro Phe Asp Gly Glu Asp Glu Asp
530 535 540
Glu Leu Phe Gln Ser Ile Met Glu His Asn Val Ser Tyr Pro Lys Ser
545 550 555 560
Leu Ser Lys Glu Ala Val Ser Ile Cys Lys Gly Leu Met Thr Lys His
565 570 575
Pro Ala Lys Arg Leu Gly Cys Gly Pro Glu Gly Glu Arg Asp Val Arg
580 585 590
Glu His Ala Phe Phe Arg Arg Ile Asp Trp Glu Lys Leu Glu Asn Arg
595 600 605
Glu Ile Gln Pro Pro Phe Lys Pro Lys Val Cys Gly Lys Gly Ala Glu
610 615 620
Asn Phe Asp Lys Phe Phe Thr Arg Gly Gln Pro Val Leu Thr Pro Pro
625 630 635 640
Asp Gln Leu Val Ile Ala Asn Ile Asp Gln Ser Asp Phe Glu Gly Phe
645 650 655
Ser Tyr Val Asn Pro Gln Phe Val His Pro Ile Leu Gln Ser Ala Val
660 665 670
<210>165
<211>671
<212>PRT
＜213〉people
<400>165
Met Ala Asp Pro Ala Ala Gly Pro Pro Pro Ser Glu Gly Glu Glu Ser
1 5 10 15
Thr Val Arg Phe Ala Arg Lys Gly Ala Leu Arg Gln Lys Asn Val His
20 25 30
Glu Val Lys Asn His Lys Phe Thr Ala Arg Phe Phe Lys Gln Pro Thr
35 40 45
Phe Cys Ser His Cys Thr Asp Phe Ile Trp Gly Phe Gly Lys Gln Gly
50 55 60
Phe Gln Cys Gln Val Cys Cys Phe Val Val His Lys Arg Cys His Glu
65 70 75 80
Phe Val Thr Phe Ser Cys Pro Gly Ala Asp Lys Gly Pro Ala Ser Asp
85 90 95
Asp Pro Arg Ser Lys His Lys Phe Lys Ile His Thr Tyr Ser Ser Pro
100 105 110
Thr Phe Cys Asp His Cys Gly Ser Leu Leu Tyr Gly Leu Ile His Gln
115 120 125
Gly Met Lys Cys Asp Thr Cys Met Met Asn Val His Lys Arg Cys Val
130 135 140
Met Asn Val Pro Ser Leu Cys Gly Thr Asp His Thr Glu Arg Arg Gly
145 150 155 160
Arg Ile Tyr Ile Gln Ala His Ile Asp Arg Asp Val Leu Ile Val Leu
165 170 175
Val Arg Asp Ala Lys Asn Leu Val Pro Met Asp Pro Asn Gly Leu Ser
180 185 190
Asp Pro Tyr Val Lys Leu Lys Leu Ile Pro Asp Pro Lys Ser Glu Ser
195 200 205
Lys Gln Lys Thr Lys Thr Ile Lys Cys Ser Leu Asn Pro Glu Trp Asn
210 215 220
Glu Thr Phe Arg Phe Gln Leu Lys Glu Ser Asp Lys Asp Arg Arg Leu
225 230 235 240
Ser Val Glu Ile Trp Asp Trp Asp Leu Thr Ser Arg Asn Asp Phe Met
245 250 255
Gly Ser Leu Ser Phe Gly Ile Ser Glu Leu Gln Lys Ala Ser Val Asp
260 265 270
Gly Trp Phe Lys Leu Leu Ser Gln Glu GluGly Glu Tyr Phe Asn Val
275 280 285
Pro Val Pro Pro Glu Gly Ser Glu Ala Asn Glu Glu Leu Arg Gln Lys
290 295 300
Phe Glu Arg Ala Lys Ile Ser Gln Gly Thr Lys Val Pro Glu Glu Lys
305 310 315 320
Thr Thr Asn Thr Val Ser Lys Phe Asp Asn Asn Gly Asn Arg Asp Arg
325 330 335
Met Lys Leu Thr Asp Phe Asn Phe Leu Met Val Leu Gly Lys Gly Ser
340 34 5350
Phe Gly Lys Val Met Leu Ser Glu Arg Lys Gly Thr Asp Glu Leu Tyr
355 360 365
Ala Val Lys Ile Leu Lys Lys Asp Val Val Ile Gln Asp Asp Asp Val
370 375 380
Glu Cys Thr Met Val Glu Lys Arg Val Leu Ala Leu Pro Gly Lys Pro
385 390 395 400
Pro Phe Leu Thr Gln Leu His Ser Cys Phe Gln Thr Met Asp Arg Leu
405 410 415
Tyr Phe Val Met Glu Tyr Val Asn Gly Gly Asp Leu Met Tyr His Ile
420 425 430
Gln Gln Val Gly Arg Phe Lys Glu Pro His Ala Val Phe Tyr Ala Ala
435 440 445
Glu Ile Ala Ile Gly Leu Phe Phe Leu Gln Ser Lys Gly Ile Ile Tyr
450 455 460
Arg Asp Leu Lys Leu Asp Asn Val Met Leu Asp Ser Glu Gly His Ile
465 470 475 480
Lys Ile Ala Asp Phe Gly Met Cys Lys Glu Asn Ile Trp Asp Gly Val
485 490 495
Thr Thr Lys Thr Phe Cys Gly Thr Pro Asp Tyr Ile Ala Pro Glu Ile
500 505 510
Ile Ala Tyr Gln Pro Tyr Gly Lys Ser Val Asp Trp Trp Ala Phe Gly
515 520 525
Val Leu Leu Tyr Glu Met Leu Ala Gly Gln Ala Pro Phe Glu Gly Glu
530 535 540
Asp Glu Asp Glu Leu Phe Gln Ser Ile Met Glu His Asn Val Ala Tyr
545 550 555 560
Pro Lys Ser Met Ser Lys Glu Ala Val Ala Ile Cys Lys Gly Leu Met
565 570 575
Thr Lys His Pro Gly Lys Arg Leu Gly Cys Gly Pro Glu Gly Glu Arg
580 585 590
Asp Ile Lys Glu His Ala Phe Phe Arg Tyr Ile Asp Trp Glu Lys Leu
595 600 605
Glu Arg Lys Glu Ile Gln Pro Pro Tyr Lys Pro Lys Ala Arg Asp Lys
610 615 620
Arg Asp Thr Ser Asn Phe Asp Lys Glu Phe Thr Arg Gln Pro Val Glu
625 630 635 640
Leu Thr Pro Thr Asp Lys Leu Phe Ile Met Asn Leu Asp Gln Asn Glu
645 650 655
Phe Ala Gly Phe Ser Tyr Thr Asn Pro Glu Phe Val Ile Asn Val
660 665 670
<210>166
<211>673
<212>PRT
＜213〉people
<400>166
Met AlaAsp Pro Ala Ala Gly Pro Pro Pro Ser Glu Gly Glu Glu Ser
1 5 10 15
Thr Val Arg Phe Ala Arg Lys Gly Ala Leu Arg Gln Lys Asn Val His
20 25 30
Glu Val Lys Asn His Lys Phe Thr Ala Arg Phe Phe Lys Gln Pro Thr
35 40 45
Phe Cys Ser His Cys Thr Asp PheIle Trp Gly Phe Gly Lys Gln Gly
50 55 60
Phe Gln Cys Gln Val Cys Cys Phe Val Val His Lys Arg Cys His Glu
65 70 75 80
Phe Val Thr Phe Ser Cys Pro Gly Ala Asp Lys Gly Pro Ala Ser Asp
85 90 95
Asp Pro Arg Ser Lys His Lys Phe Lys Ile His Thr Tyr Ser Ser Pro
100 105 110
Thr Phe Cys Asp His Cys Gly Ser Leu Leu Tyr Gly Leu Ile His Gln
115 120 125
Gly Met Lys Cys Asp Thr Cys Met Met Asn Val His Lys Arg Cys Val
130 135 140
Met Asn Val Pro Ser Leu Cys Gly Thr Asp His Thr Glu Arg Arg Gly
145 150 155 160
Arg Ile Tyr Ile Gln Ala His Ile Asp Arg Asp Val Leu Ile Val Leu
165 170 175
Val Arg Asp Ala Lys Asn Leu Val Pro Met Asp Pro Asn Gly Leu Ser
180 185 190
Asp Pro Tyr Val Lys Leu Lys Leu Ile Pro Asp Pro Lys Ser Glu Ser
195 200 205
Lys Gln Lys Thr Lys Thr Ile Lys Cys Ser Leu Asn Pro Glu Trp Asn
210 215 220
Glu Thr Phe Arg Phe Gln Leu Lys Glu Ser Asp Lys Asp Arg Arg Leu
225 230 235 240
Ser Val Glu Ile Trp Asp Trp Asp Leu Thr Ser Arg Asn Asp Phe Met
245 250 255
Gly Ser Leu Ser Phe Gly Ile Ser Glu Leu Gln Lys Ala Ser Val Asp
260 265 270
Gly Trp Phe Lys Leu Leu Ser Gln Glu Glu Gly Glu Tyr Phe Asn Val
275 280 285
Pro Val Pro Pro Glu Gly Ser Glu Ala Asn Glu Glu Leu Arg Gln Lys
290 295 300
Phe Glu Arg Ala Lys Ile Ser Gln Gly Thr Lys Val Pro Glu Glu Lys
305 310 315 320
Thr Thr Asn Thr Val Ssr Lys Phe Asp Asn Asn Gly Asn Arg Asp Arg
325 330 335
Met Lys Leu Thr Asp Phe Asn Phe Leu Met Val Leu Gly Lys Gly Ser
340 345 350
Phe Gly Lys Val Met Leu Ser Glu Arg Lys Gly Thr Asp Glu Leu Tyr
355 360 365
Ala Val Lys Ile Leu Lys Lys Asp Val Val Ile Gln Asp Asp Asp Val
370 375 380
Glu Cys Thr Met Val Glu Lys Arg Val Leu Ala Leu Pro Gly Lys Pro
385 390 395 400
Pro Phe Leu Thr Gln Leu His Ser Cys Phe Gln Thr Met Asp Arg Leu
405 410 415
Tyr Phe Val Met Glu Tyr Val Asn Gly Gly Asp Leu Met Tyr His Ile
420 425 430
Gln Gln Val Gly Arg Phe Lys Glu Pro His Ala Val Phe Tyr Ala Ala
435 440 445
Glu Ile Ala Ile Gly Leu Phe Phe Leu Gln Ser Lys Gly Ile Ile Tyr
450 455 460
Arg Asp Leu Lys Leu Asp Asn Val Met Leu Asp Ser Glu Gly His Ile
465 470 475 480
Lys Ile Ala Asp Phe Gly Met Cys Lys Glu Asn Ile Trp Asp Gly Val
485 490 495
Thr Thr Lys Thr Phe Cys Gly Thr Pro Asp Tyr Ile Ala Pro Glu Ile
500 505 510
Ile Ala Tyr Gln Pro Tyr Gly Lys Ser Val Asp Trp Trp Ala Phe Gly
515 520 525
Val Leu Leu Tyr Glu Met Leu Ala Gly Gln Ala Pro Phe Glu Gly Glu
530 535 540
Asp Glu Asp Glu Leu Phe Gln Ser Ile Met Glu His Asn Val Ala Tyr
545 550 555 560
Pro Lys Ser Met Ser Lys Glu Ala Val Ala Ile Cys Lys Gly Leu Met
565 570 575
Thr Lys His Pro Gly Lys Arg Leu Gly Cys Gly Pro Glu Gly Glu Arg
580 585 590
Asp Ile Lys Glu His Ala Phe Phe Arg Tyr Ile Asp Trp Glu Lys Leu
595 600 605
Glu Arg Lys Glu Ile Gln Pro Pro Tyr Lys Pro Lys Ala Cys Gly Arg
610 615 620
Asn Ala Glu Asn Phe Asp Arg Phe Phe Thr Arg His Pro Pro Val Leu
625 630 635 640
Thr Pro Pro Asp Gln Glu Val Ile Arg Asn Ile Asp Gln Ser Glu Phe
645 650 655
Glu Gly Phe Ser Phe Val Asn Ser Glu Phe Leu Lys Pro Glu Val Lys
660 665 670
Ser
<210>167
<211>697
<212>PRT
＜213〉people
<400>167
Met Ala Gly Leu Gly Pro Gly Val Gly Asp Ser Glu Gly Gly Pro Arg
1 5 10 15
Pro Leu Phe Cys Arg Lys Gly Ala Leu Arg Gln Lys Val Val His Glu
20 25 30
Val Lys Ser His Lys Phe Thr Ala Arg Phe Phe Lys Gln Pro Thr Phe
35 40 45
Cys Ser His Cys Thr Asp Phe Ile Trp Gly Ile Gly Lys Gln Gly Leu
50 55 60
Gln Cys Gln Val Cys Ser Phe Val Val His Arg Arg Cys His Glu Phe
65 70 75 80
Val Thr Phe Glu Cys Pro Gly Ala Gly Lys Gly Pro Gln Thr Asp Asp
85 90 95
Pro Arg Asn Lys His Lys Phe Arg Leu His Ser Tyr Ser Ser Pro Thr
100 105 110
Phe Cys Asp His Cys Gly Ser Leu Leu Tyr Gly Leu Val His Gln Gly
115 120 125
Met Lys Cys Ser Cys Cys Glu Met Asn Val His Arg Arg Cys Val Arg
130 135 140
Ser Val Pro Ser Leu Cys Gly Val Asp His Thr Glu Arg Arg Gly Arg
145 150 155 160
Leu Gln Leu Glu Ile Arg Ala Pro Thr Ala Asp Glu Ile His Val Thr
165 170 175
Val Gly Glu Ala Arg Asn Leu Ile Pro Met Asp Pro Asn Gly Leu Ser
180 185 190
Asp Pro Tyr Val Lys Leu Lys Leu Ile Pro Asp Pro Arg Asn Leu Thr
195 200 205
Lys Gln Lys Thr Arg Thr Val Lys Ala Thr Leu Asn Pro Val Trp Asn
210 215 220
Glu Thr Phe Val Phe Asn Leu Lys Pro Gly Asp Val Glu Arg Arg Leu
225 230 235 240
Ser Val Glu Val Trp Asp Trp Asp Arg Thr Ser Arg Asn Asp Phe Met
245 250 255
Gly Ala Met Ser Phe Gly Val Ser Glu Leu Leu Lys Ala Pro Val Asp
260 265 270
Gly Trp Tyr Lys Leu Leu Asn Gln Glu Glu Gly Glu Tyr Tyr Asn Val
275 280 285
Pro Val Ala Asp Ala Asp Asn Cys Ser Leu Leu Gln Lys Phe Glu Ala
290 295 300
Cys Asn Tyr Pro Leu Glu Leu Tyr Glu Arg Val Arg Met Gly Pro Ser
305 310 315 320
Ser Ser Pro Ile Pro Ser Pro Ser Pro Ser Pro Thr Asp Pro Lys Arg
325 330 335
Cys Phe Phe Gly Ala Ser Pro Gly Arg Leu His Ile Ser Asp Phe Ser
340 345 350
Phe Leu Met Val Leu Gly Lys Gly Ser Phe Gly Lys Val Met Leu Ala
355 360 365
Glu Arg Arg Gly Ser Asp Glu Leu Tyr Ala Ile Lys Ile Leu Lys Lys
370 375 380
Asp Val Ile Val Gln Asp Asp Asp Val Asp Cys Thr Leu Val Glu Lys
385 390 395 400
Arg Val Leu Ala Leu Gly Gly Arg Gly Pro Gly Gly Arg Pro His Phe
405 410 415
Leu Thr Gln Leu His Ser Thr Phe Gln Thr Pro Asp Arg Leu Tyr Phe
420 425 430
Val Met Glu Tyr Val Thr Gly Gly Asp Leu Met Tyr His Ile Gln Gln
435 440 445
Leu Gly Lys Phe Lys Glu Pro His Ala Ala Phe Tyr Ala Ala Glu Ile
450 455 460
Ala Ile Gly Leu Phe Phe Leu His Asn Gln Gly Ile Ile Tyr Arg Asp
465 470 475 480
Leu Lys Leu Asp Asn Val Met Leu Asp Ala Glu Gly His Ile Lys Ile
485 490 495
Thr Asp Phe Gly Met Cys Lys Glu Asn Val Phe Pro Gly Thr Thr Thr
500 505 510
Arg Thr Phe Cys Gly Thr Pro Asp Tyr Ile Ala Pro Glu Ile Ile Ala
515 520 525
Tyr Gln Pro Tyr Gly Lys Ser Val Asp Trp Trp Ser Phe Gly Val Leu
530 535 540
Leu Tyr Glu Met Leu Ala Gly Gln Pro Pro Phe Asp Gly Glu Asp Glu
545 550 555 560
Glu Glu Leu Phe Gln Ala Ile Met Glu Gln Thr Val Thr Tyr Pro Lys
565 570 575
Ser Leu Ser Arg Glu Ala Val Ala Ile Cys Lys Gly Phe Leu Thr Lys
580 585 590
His Pro Gly Lys Arg Leu Gly Ser Gly Pro Asp Gly Glu Pro Thr Ile
595 600 605
Arg Ala His Gly Phe Phe Arg Trp Ile Asp Trp Glu Arg Leu Glu Arg
610 615 620
Leu Glu Ile Pro Pro Pro Phe Arg Pro Arg Pro Cys Gly Arg Ser Gly
625 630 635 640
Glu Asn Phe Asp Lys Phe Phe Thr Arg Ala Ala Pro Ala Leu Thr Pro
645 650 655
Pro Asp Arg Leu Val Leu Ala Ser Ile Asp Gln Ala Asp Phe Gln Gly
660 665 670
Phe Thr Tyr Val Asn Pro Asp Phe Val His Pro Asp Ala Arg Ser Pro
675 680 685
Thr Ser Pro Val Pro Val Pro Val Met
690 695
<210>168
<211>676
<212>PRT
＜213〉people
<400>168
Met Ala Pro Phe Leu Arg Ile Ala Phe Asn Ser Tyr Glu Leu Gly Ser
1 5 10 15
Leu Gln Ala Glu Asp Glu Ala Asn Gln Pro Phe Cys Ala Val Lys Met
20 25 30
Lys Glu Ala Leu Ser Thr Glu Arg Gly Lys Thr Leu Val Gln Lys Lys
35 40 45
Pro Thr Met Tyr Pro Glu Trp Lys Ser Thr Phe Asp Ala His Ile Tyr
50 55 60
Glu Gly Arg Val Ile Gln Ile Val Leu Met Arg Ala Ala Glu Glu Pro
65 70 75 80
Val Ser Glu Val Thr Val Gly Val Ser Val Leu Ala Glu Arg Cys Lys
85 90 95
Lys Asn Asn Gly Lys Ala Glu Phe Trp Leu Asp Leu Gln Pro Gln Ala
100 105 110
Lys Val Leu Met Ser Val Gln Tyr Phe Leu Glu Asp Val Asp Cys Lys
115 120 125
Gln Ser Met Arg Ser Glu Asp Glu Ala Lys Phe Pro Thr Met Asn Arg
130 135 140
Arg Gly Ala Ile Lys Gln Ala Lys Ile His Tyr Ile Lys Asn His Glu
145 150 155 160
Phe Ile Ala Thr Phe Phe Gly Gln Pro Thr Phe Cys Ser Val Cys Lys
165 170 175
Asp Phe Val Trp Gly Leu Asn Lys Gln Gly Tyr Lys Cys Arg Gln Cys
180 185 190
Asn Ala Ala Ile His Lys Lys Cys Ile Asp Lys Ile Ile Gly Arg Cys
195 200 205
Thr Gly Thr Ala Ala Asn Ser Arg Asp Thr Ile Phe Gln Lys Glu Arg
210 215 220
Phe Asn Ile Asp Met Pro His Arg Phe Lys Val His Asn Tyr Met Ser
225 230 235 240
Pro Thr Phe Cys Asp His Cys Gly Ser Leu Leu Trp Gly Leu Val Lys
245 250 255
Gln Gly Leu Lys Cys Glu Asp Cys Gly Met Asn Val His His Lys Cys
260 265 270
Arg Glu Lys Val Ala Asn Leu Cys Gly Ile Asn Gln Lys Leu Leu Ala
275 280 285
Glu Ala Leu Asn Gln Val Thr Gln Arg Ala Ser Arg Arg Ser Asp Ser
290 295 300
Ala Ser Ser Glu Pro Val Gly Ile Tyr Gln Gly Phe Glu Lys Lys Thr
305 310 315 320
Gly Val Ala Gly Glu Asp Met Gln Asp Asn Ser Gly Thr Tyr Gly Lys
325 330 335
Ile Trp Glu Gly Ser Ser Lys Cys Asn Ile Asn Asn Phe Ile Phe His
340 345 350
Lys Val Leu Gly Lys Gly Ser Phe Gly Lys Val Leu Leu Gly Glu Leu
355 360 365
Lys Gly Arg Gly Glu Tyr Phe Ala Ile Lys Ala Leu Lys Lys Asp Val
370 375 380
Val Leu Ile Asp Asp Asp Val Glu Cys Thr Met Val Glu Lys Arg Val
385 390 395 400
Leu Thr Leu Ala Ala Glu Asn Pro Phe Leu Thr His Leu Ile Cys Thr
405 410 415
Phe Gln Thr Lys Asp His Leu Phe Phe Val Met Glu Phe Leu Asn Gly
420 425 430
Gly Asp Leu Met Tyr His Ile Gln Asp Lys Gly Arg Phe Glu Leu Tyr
435 440 445
Arg Ala Thr Phe Tyr Ala Ala Glu Ile Met Cys Gly Leu Gln Phe Leu
450 455 460
His Ser Lys Gly Ile Ile Tyr Arg Asp Leu Lys Leu Asp Asn Val Leu
465 470 475 480
Leu Asp Arg Asp Gly His Ile Lys Ile Ala Asp Phe Gly Met Cys Lys
485 490 495
Glu Asn Ile Phe Gly Glu Ser Arg Ala Ser Thr Phe Cys Gly Thr Pro
500 505 510
Asp Tyr Ile Ala Pro Glu Ile Leu Gln Gly Leu Lys Tyr Thr Phe Ser
515 520 525
Val Asp Trp Trp Ser Phe Gly Val Leu Leu Tyr Glu Met Leu Ile Gly
530 535 540
Gln Ser Pro Phe His Gly Asp Asp Glu Asp Glu Leu Phe Glu Ser Ile
545 550 555 560
Arg Val Asp Thr Pro His Tyr Pro Arg Trp Ile Thr Lys Glu Ser Lys
565 570 575
Asp Ile Leu Glu Lys Leu Phe Glu Arg Glu Pro Thr Lys Arg Leu Gly
580 585 590
Val Thr Gly Asn Ile Lys Ile His Pro Phe Phe Lys Thr Ile Asn Trp
595 600 605
Thr Leu Leu Glu Lys Arg Arg Leu Glu Pro Pro Phe Arg Pro Lys Val
610 615 620
Lys Ser Pro Arg Asp Tyr Ser Asn Phe Asp Gln Glu Phe Leu Asn Glu
625 630 635 640
Lys Ala Arg Leu Ser Tyr Ser Asp Lys Asn Leu Ile Asp Ser Met Asp
645 650 655
Gln Ser Ala Phe Ala Gly Phe Ser Phe Val Asn Pro Lys Phe Glu His
660 665 670
Leu Leu Glu Asp
675
<210>169
<211>737
<212>PRT
＜213〉people
<400>169
Met Val Val Phe Asn Gly Leu Leu Lys Ile Lys Ile Cys Glu Ala Val
1 5 10 15
Ser Leu Lys Pro Thr Ala Trp Ser Leu Arg His Ala Val Gly Pro Arg
20 25 30
Pro Gln Thr Phe Leu Leu Asp Pro Tyr Ile Ala Leu Asn Val Asp Asp
35 40 45
Ser Arg Ile Gly Gln Thr Ala Thr Lys Gln Lys Thr Asn Ser Pro Ala
50 55 60
Trp His Asp Glu Phe Val Thr Asp Val Cys Asn Gly Arg Lys Ile Glu
65 70 75 80
Leu Ala Val Phe His Asp Ala Pro Ile Gly Tyr Asp Asp Phe Val Ala
85 90 95
Asn Cys Thr Ile Gln Phe Glu Glu Leu Leu Gln Asn Gly Ser Arg His
100 105 110
Phe Glu Asp Trp Ile Asp Leu Glu Pro Glu Gly Arg Val Tyr Val Ile
115 120 125
Ile Asp Leu Ser Gly Ser Ser Gly Glu Ala Pro Lys Asp Asn Glu Glu
130 135 140
Arg Val Phe Arg Glu Arg Met Arg Pro Arg Lys Arg Gln Gly Ala Val
145 150 155 160
Arg Arg Arg Val His Gln Val Asn Gly His Lys Phe Met Ala Thr Tyr
165 170 175
Leu Arg Gln Pro Thr Tyr Cys Ser His Cys Arg Asp Phe Ile Trp Gly
180 185 190
Val Ile Gly Lys Gln Gly Tyr Gln Cys Gln Val Cys Thr Cys Val Val
195 200 205
His Lys Arg Cys His Glu Leu Ile Ile Thr Lys Cys Ala Gly Leu Lys
210 215 220
Lys Gln Glu Thr Pro Asp Gln Val Gly Ser Gln Arg Phe Ser Val Asn
225 230 235 240
Met Pro His Lys Phe Gly Ile His Asn Tyr Lys Val Pro Thr Phe Cys
245 250 255
Asp His Cys Gly Ser Leu Leu Trp Gly Leu Leu Arg Gln Gly Leu Gln
260 265 270
Cys Lys Val Cys Lys Met Asn Val His Arg Arg Cys Glu Thr Asn Val
275 280 285
Ala Pro Asn Cys Gly Val Asp Ala Arg Gly Ile Ala Lys Val Leu Ala
290 295 300
Asp Leu Gly Val Thr Pro Asp Lys Ile Thr Asn Ser Gly Gln Arg Arg
305 310 315 320
Lys Lys Leu Ile Ala Gly Ala Glu Ser Pro Gln Pro Ala Ser Gly Ser
325 330 335
Ser Pro Ser Glu Glu Asp Arg Ser Lys Ser Ala Pro Thr Ser Pro Cys
340 345 350
Asp Gln Glu Ile Lys Glu Leu Glu Asn Asn Ile Arg Lys Ala Leu Ser
355 360 365
Phe Asp Asn Arg Gly Glu Glu His Arg Ala Ala Ser Ser Pro Asp Gly
370 375 380
Gln Leu Met Ser Pro Gly Glu Asn Gly Glu Val Arg Gln Gly Gln Ala
385 390 395 400
Lys Arg Leu Gly Leu Asp Glu Phe Asn Phe Ile Lys Val Leu Gly Lys
405 410 415
Gly Ser Phe Gly Lys Val Met Leu Ala Glu Leu Lys Gly Lys Asp Glu
420 425 430
Val Tyr Ala Val Lys Val Leu Lys Lys Asp Val Ile Leu Gln Asp Asp
435 440 445
Asp Val Asp Cys Thr Met Thr Glu Lys Arg Ile Leu Ala Leu Ala Arg
450 455 460
Lys His Pro Tyr Leu Thr Gln Leu Tyr Cys Cys Phe Gln Thr Lys Asp
465 470 475 480
Arg Leu Phe Phe Val Met Glu Tyr Val Asn Gly Gly Asp Leu Met Phe
485 490 495
Gln Ile Gln Arg Ser Arg Lys Phe Asp Glu Pro Arg Ser Arg Phe Tyr
500 505 510
Ala Ala Glu Val Thr Ser Ala Leu Met Phe Leu His Gln His Gly Val
515 520 525
Ile Tyr Arg Asp Leu Lys Leu Asp Asn Ile Leu Leu Asp Ala Glu Gly
530 535 540
His Cys Lys Leu Ala Asp Phe Gly Met Cys Lys Glu Gly Ile Leu Asn
545 550 555 560
Gly Val Thr Thr Thr Thr Phe Cys Gly Thr Pro Asp Tyr Ile Ala Pro
565 570 575
Glu Ile Leu Gln Glu Leu Glu Tyr Gly Pro Ser Val Asp Trp Trp Ala
580 585 590
Leu Gly Val Leu Met Tyr Glu Met Met Ala Gly Gln Pro Pro Phe Glu
595 600 605
Ala Asp Asn Glu Asp Asp Leu Phe Glu Ser Ile Leu His Asp Asp Val
610 615 620
Leu Tyr Pro Val Trp Leu Ser Lys Glu Ala Val Ser Ile Leu Lys Ala
625 630 635 640
Phe Met Thr Lys Asn Pro His Lys Arg Leu Gly Cys Val Ala Ser Gln
645 650 655
Asn Gly Glu Asp Ala Ile Lys Gln His Pro Phe Phe Lys Glu Ile Asp
660 665 670
Trp Val Leu Leu Glu Gln Lys Lys Ile Lys Pro Pro Phe Lys Pro Arg
675 680 685
Ile Lys Thr Lys Arg Asp Val Asn Asn Phe Asp Gln Asp Phe Thr Arg
690 695 700
Glu Glu Pro Val Leu Thr Leu Val Asp Glu Ala Ile Val Lys Gln Ile
705 710 715 720
Asn Gln Glu Glu Phe Lys Gly Phe Ser Tyr Phe Gly Glu Asp Leu Met
725 730 735
Pro
<210>170
<211>682
<212>PRT
＜213〉people
<400>170
Met Ser Ser Gly Thr Met Lys Phe Asn Gly Tyr Leu Arg Val Arg Ile
1 5 10 15
Gly Glu Ala Val Gly Leu Gln Pro Thr Arg Trp Ser Leu Arg His Ser
20 25 30
Leu Phe Lys Lys Gly His Gln Leu Leu Asp Pro Tyr Leu Thr Val Ser
35 40 45
Val Asp Gln Val Arg Val Gly Gln Thr Ser Thr Lys Gln Lys Thr Asn
50 55 60
Lys Pro Thr Tyr Asn Glu Glu Phe Cys Ala Asn Val Thr Asp Gly Gly
65 70 75 80
His Leu Glu Leu Ala Val Phe His Glu Thr Pro Leu Gly Tyr Asp Phe
85 90 95
Val Ala Asn Cys Thr Leu Gln Phe Gln Glu Leu Val Gly Thr Thr Gly
100 105 110
Ala Ser Asp Thr Phe Glu Gly Trp Val Asp Leu Glu Pro Glu Gly Lys
115 120 125
Val Phe Val Val Ile Thr Leu Thr Gly Ser Phe Thr Glu Ala Thr Leu
130 135 140
Gln Arg Asp Arg Ile Phe Lys His Phe Thr Arg Lys Arg Gln Arg Ala
145 150 155 160
Met Arg Arg Arg Val His Gln Ile Asn Gly His Lys Phe Met Ala Thr
165 170 175
Tyr Leu Arg Gln Pro Thr Tyr Cys Ser His Cys Arg Glu Phe Ile Trp
180 185 190
Gly Val Phe Gly Lys Gln Gly Tyr Gln Cys Gln Val Cys Thr Cys Val
195 200 205
Val His Lys Arg Cys His His Leu Ile Val Thr Ala Cys Thr Cys Gln
210 215 220
Asn Asn Ile Asn Lys Val Asp Ser Lys Ile Ala Glu Gln Arg Phe Gly
225 230 235 240
Ile Asn Ile Pro His Lys Phe Ser Ile His Asn Tyr Lys Val Pro Thr
245 250 255
Phe Cys Asp His Cys Gly Ser Leu Leu Trp Gly Ile Met Arg Gln Gly
260 265 270
Leu Gln Cys Lys Ile Cys Lys Met Asn Val His Ile Arg Cys Gln Ala
275 280 285
Asn Val Ala Pro Asn Cys Gly Val Asn Ala Val Glu Leu Ala Lys Thr
290 295 300
Leu Ala Gly Met Gly Leu Gln Pro Gly Asn Ile Ser Pro Thr Ser Lys
305 310 315 320
Leu Val Ser Arg Ser Thr Leu Arg Arg Gln Gly Lys Glu Ser Ser Lys
325 330 335
Glu Gly Asn Gly Ile Gly Val Asn Ser Ser Asn Arg Leu Gly Ile Asp
340 345 350
Asn Phe Glu Phe Ile Arg Val Leu Gly Lys Gly Ser Phe Gly Lys Val
355 360 365
Met Leu Ala Arg Val Lys Glu Thr Gly Asp Leu Tyr Ala Val Lys Val
370 375 380
Leu Lys Lys Asp Val Ile Leu Leu Asp Asp Asp Val Glu Cys Thr Met
385 390 395 400
Thr Glu Lys Arg Ile Leu Ser Leu Ala Arg Asn His Pro Phe Leu Thr
405 410 415
Gln Leu Phe Cys Cys Phe Gln Thr Pro Asp Arg Leu Phe Phe Val Met
420 425 430
Glu Phe Val Asn Gly Gly Asp Leu Met Phe His Ile Gln Lys Ser Arg
435 440 445
Arg Phe Asp Glu Ala Arg Ala Arg Phe Tyr Ala Ala Glu Ile Ile Ser
450 455 460
Ala Leu Met Phe Leu His Asp Lys Gly Ile Ile Tyr Arg Asp Leu Lys
465 470 475 480
Leu Asp Asn Val Leu Leu Asp His Glu Gly His Cys Lys Leu Ala Asp
485 490 495
Phe Gly Met Cys Lys Glu Gly Ile Cys Asn Gly Val Thr Thr Ala Thr
500 505 510
Phe Cys Gly Thr Pro Asp Tyr Ile Ala Pro Glu Ile Leu Gln Glu Met
515 520 525
Leu Tyr Gly Pro Ala Val Asp Trp Trp Ala Met Gly Val Leu Leu Tyr
530 535 540
Glu Met Leu Cys Gly His Ala Pro Phe Glu Ala Glu Asn Glu Asp Asp
545 550 555 560
Leu Phe Glu Ala Ile Leu Asn Asp Glu Val Val Tyr Pro Thr Trp Leu
565 570 575
His Glu Asp Ala Thr Gly Ile Leu Lys Ser Phe Met Thr Lys Asn Pro
580 585 590
Thr Met Arg Leu Gly Ser Leu Thr Gln Gly Gly Glu His Ala Ile Leu
595 600 605
Arg His Pro Phe Phe Lys Glu Ile Asp Trp Ala Gln Leu Asn His Arg
610 615 620
Gln Ile Glu Pro Pro Phe Arg Pro Arg Ile Lys Ser Arg Glu Asp Val
625 630 635 640
Ser Asn Phe Asp Pro Asp Phe Ile Lys Glu Glu Pro Val Leu Thr Pro
645 650 655
Ile Asp Glu Gly His Leu Pro Met Ile Asn Gln Asp Glu Phe Arg Asn
660 665 670
Phe Ser Tyr Val Ser Pro Glu Leu Gln Pro
675 680
<210>171
<211>706
<212>PRT
＜213〉people
<400>171
Met Ser Pro Phe Leu Arg Ile Gly Leu Ser Asn Phe Asp Cys Gly Ser
1 5 10 15
Cys Gln Ser Cys Gln Gly Glu Ala Val Asn Pro Tyr Cys Ala Val Leu
20 25 30
Val Lys Glu Tyr Val Glu Ser Glu Asn Gly Gln Met Tyr Ile Gln Lys
35 40 45
Lys Pro Thr Met Tyr Pro Pro Trp Asp Ser Thr Phe Asp Ala His Ile
50 55 60
Asn Lys Gly Arg Val Met Gln Ile Ile Val Lys Gly Lys Asn Val Asp
65 70 75 80
Leu Ile Ser Glu Thr Thr Val Glu Leu Tyr Ser Leu Ala Glu Arg Cys
85 90 95
Arg Lys Asn Asn Gly Lys Thr Glu Ile Trp Leu Glu Leu Lys Pro Gln
100 105 110
Gly Arg Met Leu Met Asn Ala Arg Tyr Phe Leu Glu Met Ser Asp Thr
115 120 125
Lys Asp Met Asn Glu Phe Glu Thr Glu Gly Phe Phe Ala Leu His Gln
130 135 140
Arg Arg Gly Ala Ile Lys Gln Ala Lys Val His His Val Lys Cys His
145 150 155 160
Glu Phe Thr Ala Thr Phe Phe Pro Gln Pro Thr Phe Cys Ser Val Cys
165 170 175
His Glu Phe Val Trp Gly Leu Asn Lys Gln Gly Tyr Gln Cys Arg Gln
180 185 190
Cys Asn Ala Ala Ile His Lys Lys Cys Ile Asp Lys Val Ile Ala Lys
195 200 205
Cys Thr Gly Ser Ala Ile Asn Ser Arg Glu Thr Met Phe His Lys Glu
210 215 220
Arg Phe Lys Ile Asp Met Pro His Arg Phe Lys Val Tyr Asn Tyr Lys
225 230 235 240
Ser Pro Thr Phe Cys Glu His Cys Gly Thr Leu Leu Trp Gly Leu Ala
245 250 255
Arg Gln Gly Leu Lys Cys Asp Ala Cys Gly Met Asn Val His His Arg
260 265 270
Cys Gln Thr Lys Val Ala Asn Leu Cys Gly Ile Asn Gln Lys Leu Met
275 280 285
Ala Glu Ala Leu Ala Met Ile Glu Ser Thr Gln Gln Ala Arg Cys Leu
290 295 300
Arg Asp Thr Glu Gln Ile Phe Arg Glu Gly Pro Val Glu Ile Gly Leu
305 310 315 320
Pro Cys Ser Ile Lys Asn Glu Ala Arg Pro Pro Cys Leu Pro Thr Pro
325 330 335
Gly Lys Arg Glu Pro Gln Gly Ile Ser Trp Glu Ser Pro Leu Asp Glu
340 345 350
Val Asp Lys Met Cys His Leu Pro Glu Pro Glu Leu Asn Lys Glu Arg
355 360 365
Pro Ser Leu Gln Ile Lys Leu Lys Ile Glu Asp Phe Ile Leu His Lys
370 375 380
Met Leu Gly Lys Gly Ser Phe Gly Lys Val Phe Leu Ala Glu Phe Lys
385 390 395 400
Lys Thr Asn Gln Phe Phe Ala Ile Lys Ala Leu Lys Lys Asp Val Val
405 410 415
Leu Met Asp Asp Asp Val Glu Cys Thr Met Val Glu Lys Arg Val Leu
420 425 430
Ser Leu Ala Trp Glu His Pro Phe Leu Thr His Met Phe Cys Thr Phe
435 440 445
Gln Thr Lys Glu Asn Leu Phe Phe Val Met Glu Tyr Leu Asn Gly Gly
450 455 460
Asp Leu Met Tyr His Ile Gln Ser Cys His Lys Phe Asp Leu Ser Arg
465 470 475 480
Ala Thr Phe Tyr Ala Ala Glu Ile Ile Leu Gly Leu Gln Phe Leu His
485 490 495
Ser Lys Gly Ile Val Tyr Arg Asp Leu Lys Leu Asp Asn Ile Leu Leu
500 505 510
Asp Lys Asp Gly His Ile Lys Ile Ala Asp Phe Gly Met Cys Lys Glu
515 520 525
Asn Met Leu Gly Asp Ala Lys Thr Asn Thr Phe Cys Gly Thr Pro Asp
530 535 540
Tyr Ile Ala Pro Glu Ile Leu Leu Gly Gln Lys Tyr Asn His Ser Val
545 550 555 560
Asp Trp Trp Ser Phe Gly Val Leu Leu Tyr Glu Met Leu Ile Gly Gln
565 570 575
Ser Pro Phe His Gly Gln Asp Glu Glu Glu Leu Phe His Ser Ile Arg
580 585 590
Met Asp Asn Pro Phe Tyr Pro Arg Trp Leu Glu Lys Glu Ala Lys Asp
595 600 605
Leu Leu Val Lys Leu Phe Val Arg Glu Pro Glu Lys Arg Leu Gly Val
610 615 620
Arg Gly Asp Ile Arg Gln His Pro Leu Phe Arg Glu Ile Asn Trp Glu
625 630 635 640
Glu Leu Glu Arg Lys Glu Ile Asp Pro Pro Phe Arg Pro Lys Val Lys
645 650 655
Ser Pro Phe Asp Cys Ser Asn Phe Asp Lys Glu Phe Leu Asn Glu Lys
660 665 670
Pro Arg Leu Ser Phe Ala Asp Arg Ala Leu Ile Asn Ser Met Asp Gln
675 680 685
Asn Met Phe Arg Asn Phe Ser Phe Met Asn Pro Gly Met Glu Arg Leu
690 695 700
Glu Ser
705
<210>172
<211>587
<212>PRT
＜213〉people
<400>172
Met Ser His Thr Val Ala Gly Gly Gly Ser Gly Asp His Ser His Gln
1 5 10 15
Val Arg Val Lys Ala Tyr Tyr Arg Gly Asp Ile Met Ile Thr His Phe
20 25 30
Glu Pro Ser Ile Ser Phe Glu Gly Leu Cys Asn Glu Val Arg Asp Met
35 40 45
Cys Ser Phe Asp Asn Glu Gln Leu Phe Thr Met Lys Trp Ile Asp Glu
50 55 60
Glu Gly Asp Pro Cys Thr Val Ser Ser Gln Leu Glu Leu Glu Glu Ala
65 70 75 80
Phe Arg Leu Tyr Glu Leu Asn Lys Asp Ser Glu Leu Leu Ile His Val
85 90 95
Phe Pro Cys Val Pro Glu Arg Pro Gly Met Pro Cys Pro Gly Glu Asp
100 105 110
Lys Ser Ile Tyr Arg Arg Gly Ala Arg Arg Trp Arg Lys Leu Tyr Cys
115 120 125
Ala Asn Gly His Thr Phe Gln Ala Lys Arg Phe Asn Arg Arg Ala His
130 135 140
Cys Ala Ile Cys Thr Asp Arg Ile Trp Gly Leu Gly Arg Gln Gly Tyr
145 150 155 160
Lys Cys Ile Asn Cys Lys Leu Leu Val His Lys Lys Cys His Lys Leu
165 170 175
Val Thr Ile Glu Cys Gly Arg His Ser Leu Pro Gln Glu Pro Val Met
180 185 190
Pro Met Asp Gln Ser Ser Met His Ser Asp His Ala Gln Thr Val Ile
195 200 205
Pro Tyr Asn Pro Ser Ser His Glu Ser Leu Asp Gln Val Gly Glu Glu
210 215 220
Lys Glu Ala Met Asn Thr Arg Glu Ser Gly Lys Ala Ser Ser Ser Leu
225 230 235 240
Gly Leu Gln Asp Phe Asp Leu Leu Arg Val Ile Gly Arg Gly Ser Tyr
245 250 255
Ala Lys Val Leu Leu Val Arg Leu Lys Lys Thr Asp Arg Ile Tyr Ala
260 265 270
Met Lys Val Val Lys Lys Glu Leu Val Asn Asp Asp Glu Asp Ile Asp
275 280 285
Trp Val Gln Thr Glu Lys His Val Phe Glu Gln Ala Ser Asn His Pro
290 295 300
Phe Leu Val Gly Leu His Ser Cys Phe Gln Thr Glu Ser Arg Leu Phe
305 310 315 320
Phe Val Ile Glu Tyr Val Asn Gly Gly Asp Leu Met Phe His Met Gln
325 330 335
Arg Gln Arg Lys Leu Pro Glu Glu His Ala Arg Phe Tyr Ser Ala Glu
340 345 350
Ile Ser Leu Ala Leu Asn Tyr Leu His Glu Arg Gly Ile Ile Tyr Arg
355 360 365
Asp Leu Lys Leu Asp Asn Val Leu Leu Asp Ser Glu Gly His Ile Lys
370 375 380
Leu Thr Asp Tyr Gly Met Cys Lys Glu Gly Leu Arg Pro Gly Asp Thr
385 390 395 400
Thr Ser Thr Phe Cys Gly Thr Pro Asn Tyr Ile Ala Pro Glu Ile Leu
405 410 415
Arg Gly Glu Asp Tyr Gly Phe Ser Val Asp Trp Trp Ala Leu Gly Val
420 425 430
Leu Met Phe Glu Met Met Ala Gly Arg Ser Pro Phe Asp Ile Val Gly
435 440 445
Ser Ser Asp Asn Pro Asp Gln Asn Thr Glu Asp Tyr Leu Phe Gln Val
450 455 460
Ile Leu Glu Lys Gln Ile Arg Ile Pro Arg Ser Leu Ser Val Lys Ala
465 470 475 480
Ala Ser Val Leu Lys Ser Phe Leu Asn Lys Asp Pro Lys Glu Arg Leu
485 490 495
Gly Cys His Pro Gln Thr Gly Phe Ala Asp Ile Gln Gly His Pro Phe
500 505 510
Phe Arg Asn Val Asp Trp Asp Met Met Glu Gln Lys Gln Val Val Pro
515 520 525
Pro Phe Lys Pro Asn Ile Ser Gly Glu Phe Gly Leu Asp Asn Phe Asp
530 535 540
Ser Gln Phe Thr Asn Glu Pro Val Gln Leu Thr Pro Asp Asp Asp Asp
545 550 555 560
Ile Val Arg Lys Ile Asp Gln Ser Glu Phe Glu Gly Phe Glu Tyr Ile
565 570 575
Asn Pro Leu Leu Met Ser Ala Glu Glu Cys Val
580 585
<210>173
<211>912
<212>PRT
＜213〉people
<400>173
Met Ser Ala Pro Pro Val Leu Arg Pro Pro Ser Pro Leu Leu Pro Val
1 5 10 15
Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Leu Val Pro Gly Ser Gly
20 25 30
Pro Gly Pro Ala Pro Phe Leu Ala Pro Val Ala Ala Pro Val Gly Gly
35 40 45
Ile Ser Phe His Leu Gln Ile Gly Leu Ser Arg Glu Pro Val Leu Leu
50 55 60
Leu Gln Asp Ser Ser Gly Asp Tyr Ser Leu Ala His Val Arg Glu Met
65 70 75 80
Ala Cys Ser Ile Val Asp Gln Lys Phe Pro Glu Cys Gly Phe Tyr Gly
85 90 95
Met Tyr Asp Lys Ile Leu Leu Phe Arg His Asp Pro Thr Ser Glu Asn
100 105 110
Ile Leu Gln Leu Val Lys Ala Ala Ser Asp Ile Gln Glu Gly Asp Leu
115 120 125
Ile Glu Val Val Leu Ser Arg Ser Ala Thr Phe Glu Asp Phe Gln Ile
130 135 140
Arg Pro His Ala Leu Phe Val His Ser Tyr Arg Ala Pro Ala Phe Cys
145 150 155 160
Asp His Cys Gly Glu Met Leu Trp Gly Leu Val Arg Gln Gly Leu Lys
165 170 175
Cys Glu Gly Cys Gly Leu Asn Tyr His Lys Arg Cys Ala Phe Lys Ile
180 185 190
Pro Asn Asn Cys Ser Gly Val Arg Arg Arg Arg Leu Ser Asn Val Ser
195 200 205
Leu Thr Gly Val Ser Thr Ile Arg Thr Ser Ser Ala Glu Leu Ser Thr
210 215 220
Ser Ala Pro Asp Glu Pro Leu Leu Gln Lys Ser Pro Ser Glu Ser Phe
225 230 235 240
Ile Gly Arg Glu Lys Arg Ser Asn Ser Gln Ser Tyr Ile Gly Arg Pro
245 250 255
Ile His Leu Asp Lys Ile Leu Met Ser Lys Val Lys Val Pro His Thr
260 265 270
Phe Val Ile His Ser Tyr Thr Arg Pro Thr Val Cys Gln Tyr Cys Lys
275 280 285
Lys Leu Leu Lys Gly Leu Phe Arg Gln Gly Leu Gln Cys Lys Asp Cys
290 295 300
Arg Phe Asn Cys His Lys Arg Cys Ala Pro Lys Val Pro Asn Asn Cys
305 310 315 320
Leu Gly Glu Val Thr Ile Asn Gly Asp Leu Leu Ser Pro Gly Ala Glu
325 330 335
Ser Asp Val Val Met Glu Glu Gly Ser Asp Asp Asn Asp Ser Glu Arg
340 345 350
Asn Ser Gly Leu Met Asp Asp Met Glu Glu Ala Met Val Gln Asp Ala
355 360 365
Glu Met Ala Met Ala Glu Cys Gln Asn Asp Ser Gly Glu Met Gln Asp
370 375 380
Pro Asp Pro Asp His Glu Asp Ala Asn Arg Thr Ile Ser Pro Ser Thr
385 390 395 400
Ser Asn Asn Ile Pro Leu Met Arg Val Val Gln Ser Val Lys His Thr
405 410 415
Lys Arg Lys Ser Ser Thr Val Met Lys Glu Gly Trp Met Val His Tyr
420 425 430
Thr Ser Lys Asp Thr Leu Arg Lys Arg His Tyr Trp Arg Leu Asp Ser
435 440 445
Lys Cys Ile Thr Leu Phe Gln Asn Asp Thr Gly Ser Arg Tyr Tyr Lys
450 455 460
Glu Ile Pro Leu Ser Glu Ile Leu Ser Leu Glu Pro Val Lys Thr Ser
465 470 475 480
Ala Leu Ile Pro Asn Gly Ala Asn Pro His Cys Phe Glu Ile Thr Thr
485 490 495
Ala Asn Val Val Tyr Tyr Val Gly Glu Asn Val Val Asn Pro Ser Ser
500 505 510
Pro Ser Pro Asn Asn Ser Val Leu Thr Ser Gly Val Gly Ala Asp Val
515 520 525
Ala Arg Met Trp Glu Ile Ala Ile Gln His Ala Leu Met Pro Val Ile
530 535 540
Pro Lys Gly Ser Ser Val Gly Thr Gly Thr Asn Leu His Arg Asp Ile
545 550 555 560
Ser Val Ser Ile Ser Val Ser Asn Cys Gln Ile Gln Glu Asn Val Asp
565 570 575
Ile Ser Thr Val Tyr Gln Ile Phe Pro Asp Glu Val Leu Gly Ser Gly
580 585 590
Gln Phe Gly Ile Val Tyr Gly Gly Lys His Arg Lys Thr Gly Arg Asp
595 600 605
Val Ala Ile Lys Ile Ile Asp Lys Leu Arg Phe Pro Thr Lys Gln Glu
610 615 620
Ser Gln Leu Arg Asn Glu Val Ala Ile Leu Gln Asn Leu His His Pro
625 630 635 640
Gly Val Val Asn Leu Glu Cys Met Phe Glu Thr Pro Glu Arg Val Phe
645 650 655
Val Val Met Glu Lys Leu His Gly Asp Met Leu Glu Met Ile Leu Ser
660 665 670
Ser Glu Lys Gly Arg Leu Pro Glu His Ile Thr Lys Phe Leu Ile Thr
675 680 685
Gln Ile Leu Val Ala Leu Arg His Leu His Phe Lys Asn Ile Val His
690 695 700
Cys Asp Leu Lys Pro Glu Asn Val Leu Leu Ala Ser Ala Asp Pro Phe
705 710 715 720
Pro Gln Val Lys Leu Cys Asp Phe Gly Phe Ala Arg Ile Ile Gly Glu
725 730 735
Lys Ser Phe Arg Arg Ser Val Val Gly Thr Pro Ala Tyr Leu Ala Pro
740 745 750
Glu Val Leu Arg Asn Lys Gly Tyr Asn Arg Ser Leu Asp Met Trp Ser
755 760 765
Val Gly Val Ile Ile Tyr Val Ser Leu Ser Gly Thr Phe Pro Phe Asn
770 775 780
Glu Asp Glu Asp Ile His Asp Gln Ile Gln Asn Ala Ala Phe Met Tyr
785 790 795 800
Pro Pro Asn Pro Trp Lys Glu Ile Ser His Glu Ala Ile Asp Leu Ile
805 810 815
Asn Asn Leu Leu Gln Val Lys Met Arg Lys Arg Tyr Ser Val Asp Lys
820 825 830
Thr Leu Ser His Pro Trp Leu Gln Asp Tyr Gln Thr Trp Leu Asp Leu
835 840 845
Arg Glu Leu Glu Cys Lys Ile Gly Glu Arg Tyr Ile Thr His Glu Ser
850 855 860
Asp Asp Leu Arg Trp Glu Lys Tyr Ala Gly Glu Gln Arg Leu Gln Tyr
865 870 875 880
Pro Thr His Leu Ile Asn Pro Ser Ala Ser His Ser Asp Thr Pro Glu
885 890 895
Thr Glu Glu Thr Glu Met Lys Ala Leu Gly Glu Arg Val Ser Ile Leu
900 905 910

Claims (12)

1. pharmaceutical preparation comprises
Chemistry attaches to the protein kinase C of transit peptides and regulates peptide; With
Sugar, wherein said sugar and this peptide/transit peptides bond are to exist from about 100: 1 to about 1: 1 ratio.
2. the described preparation of claim 1, wherein said sugar is selected from fructose, lactose, D-mannose and mannitol.
3. the described preparation of claim 1, wherein said ratio was from about 80: 1 to about 8: 1.
4. the described preparation of claim 1, wherein said ratio was from about 80: 1 to about 5: 1.
5. the described preparation of claim 1, wherein said transit peptides is the peptide that contains pR60.
6. the described preparation of claim 1, wherein said transit peptides is the HIV-tat peptide.
7. the described preparation of claim 1, wherein said preparation is freeze-drying.
8. the described preparation of claim 1, wherein said adjusting peptide is SEQ ID NO:2-162 or 163.
9. the described preparation of claim 8, wherein said adjusting peptide is SEQ ID NO:33.
10. the described preparation of claim 9, the described ratio of wherein said sugar and described adjusting peptide is about 5: 1.
11. the described preparation of claim 1, wherein said preparation is suitable for the parenteral approach.
12. the described preparation of claim 1, wherein said parenteral approach are administrations in the hat.
CNA2006800361338A 2005-09-30 2006-07-13 Pharmaceutical formulation Pending CN101277611A (en)

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US20060153867A1 (en) 2006-07-13
JP2013100329A (en) 2013-05-23
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